chr12-106427339-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP2PP5BS1_Supporting

The NM_018082.6(POLR3B):c.1244T>C(p.Met415Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000871 in 1,613,792 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00089 ( 1 hom. )

Consequence

POLR3B
NM_018082.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:9O:1

Conservation

PhyloP100: 7.52

Variant links:

Genes affected

POLR3B (HGNC:30348): (RNA polymerase III subunit B) This gene encodes the second largest subunit of RNA polymerase III, the polymerase responsible for synthesizing transfer and small ribosomal RNAs in eukaryotes. The largest subunit and the encoded protein form the catalytic center of RNA polymerase III. Mutations in this gene are a cause of hypomyelinating leukodystrophy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

POLR3B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP2

Missense variant in the POLR3B gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 3.1978 (above the threshold of 3.09). Trascript score misZ: 3.4842 (above the threshold of 3.09). GenCC associations: The gene is linked to hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome, Charcot-Marie-Tooth disease, demyelinating, IIA 1I, hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, endosteal sclerosis-cerebellar hypoplasia syndrome.

PP5

Variant 12-106427339-T-C is Pathogenic according to our data. Variant chr12-106427339-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285205.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=8, Pathogenic=4, not_provided=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000643 (98/152328) while in subpopulation NFE AF= 0.00134 (91/68032). AF 95% confidence interval is 0.00112. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3B	NM_018082.6 link	c.1244T>C	p.Met415Thr	missense_variant	Exon 13 of 28	ENST00000228347.9	NP_060552.4	Q9NW08-1Q7Z3R8
POLR3B	NM_001160708.2 link	c.1070T>C	p.Met357Thr	missense_variant	Exon 13 of 28		NP_001154180.1	Q9NW08-2
POLR3B	XM_017019621.3 link	c.1244T>C	p.Met415Thr	missense_variant	Exon 13 of 26		XP_016875110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
POLR3B	ENST00000228347.9 link	c.1244T>C	p.Met415Thr	missense_variant	Exon 13 of 28	1	NM_018082.6	ENSP00000228347.4	Q9NW08-1
POLR3B	ENST00000539066.5 link	c.1070T>C	p.Met357Thr	missense_variant	Exon 13 of 28	2		ENSP00000445721.1	Q9NW08-2
POLR3B	ENST00000549569.1 link	c.*9T>C		downstream_gene_variant		4		ENSP00000448398.1	F8VRU2
POLR3B	ENST00000549195.1 link	n.*72T>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000554

AC:

139

AN:

251068

Hom.:

AF XY:

0.000553

AC XY:

AN XY:

135658

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00115

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000895

AC:

1308

AN:

1461464

Hom.:

Cov.:

AF XY:

0.000851

AC XY:

619

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.00114

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.000643

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00134

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00115

Hom.:

Bravo

AF:

0.000578

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000618

AC:

EpiCase

AF:

0.00158

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:9Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:3

Mar 07, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35316923, 27512013, 33726816, 34440436, 32870266, 27029625, 25133958, 32345981, 22855961, 37273706, 36268624) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 30, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 415 of the POLR3B protein (p.Met415Thr). This variant is present in population databases (rs199504211, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of autosomal recessive POLR3B-related conditions (PMID: 25133958, 27029625, 27512013, 34440436, 36268624, 37273706). ClinVar contains an entry for this variant (Variation ID: 285205). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLR3B protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jul 12, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, PP3, PM3_strong -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLR3B: PM3:Very Strong, PM2:Supporting, PP2 -

Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism

Pathogenic:3Uncertain:2Other:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Met415Thr variant in POLR3B has been reported in 7 individuals with 4H leukodystrophy (PMID: 27512013, 25133958, 27029625, 33726816, 34440436, 31996231) and has been identified in 0.11% (149/128840) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs199504211). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 285205) and has been interpreted as VUS by Eurofins NTD (LLC) and Fulgent Genetics, and likely pathogenic or pathogenic by Institute of Human Genetics (University of Leipzig Medical Center), Institute of Medical Genetics and Applied Genomics (University Hospital T√ºbingen), GeneDx, and GeneReviews. Of the 7 affected individuals, 2 were compound heterozygotes that carried reported pathogenic variants in trans and with unknown phase, which increases the likelihood that the p.Met415Thr variant is pathogenic (VariationID: 620581; PMID: 31996231, 27512013). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in POLR3B in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, the clinical significance of the p.Met415Thr variant is uncertain. ACMG/AMP Criteria applied: PP3, PM3, PP2 (Richards 2015). -

May 30, 2022

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Inborn genetic diseases

Pathogenic:1

Aug 04, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1244T>C (p.M415T) alteration is located in exon 13 (coding exon 13) of the POLR3B gene. This alteration results from a T to C substitution at nucleotide position 1244, causing the methionine (M) at amino acid position 415 to be replaced by a threonine (T)._x000D_ _x000D_ Based on the available evidence, the c.1244T>C p.M415T alteration is classified as likely pathogenic for autosomal recessive POLR3B-related hypomyelinating leukodystrophy; however, it is unlikely to be causative of autosomal dominant POLR3B-related Charcot-Marie-Tooth disease type 1. Based on data from gnomAD, the C allele has an overall frequency of 0.06% (160/282446) total alleles studied. The highest observed frequency was 0.12% (149/128840) of European (non-Finnish) alleles. This variant has been reported to be compound heterozygous with other POLR3B variants in multiple individuals with features consistent with POLR3B-related hypomyelinating leukodystrophy (Fogel, 2014; La Piana, 2016; Richards, 2017; Barbosa-Gouveia, 2021; Gach, 2022). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

See cases

Pathogenic:1

Nov 16, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4, PM3, PP3 -

Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism;C5676914:Charcot-Marie-Tooth disease, demyelinating, IIA 1I

Pathogenic:1

Apr 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Mar 13, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POLR3B c.1244T>C (p.Met415Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00055 in 251068 control chromosomes. c.1244T>C has been reported in the literature in individuals affected with POLR3-Related Leukodystrophy, cerebellar ataxia, isolated hypogonadotropic hypogonadism (Barbosa-Gouveia_2021, Fogel_2014, Richards_2017) and in an individual with clinical features of ataxia, myopia, developmental delay, short stature, and cerebellar atrophy (La Piana_2016). In all cases, the second allele reported in the patients were of unknown or uncertain significance. These reports do not provide unequivocal conclusions about association of the variant with POLR3-Related Leukodystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. Multiple laboratories reported the variant with conflicting assessments including uncertain significance (n=5), likely pathogenic (n=4), or pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Amenorrhea

Uncertain:1

Mar 08, 2021

Yale Center for Mendelian Genomics, Yale University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

POLR-related leukodystrophy

Uncertain:1

Sep 14, 2023

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The POLR3B c.1244T>C (p.Met415Thr) missense variant has been reported in at least five individuals with variable presentations of POLR3-related conditions, including ataxia, hypogonadotropic hypogonadism, white matter abnormalities on brain MRI, and myopia (PMID: 25133958; 27029625; 27512013; 33726816; 34440436). In two of these cases, the variant co-occurred with a predicted loss of function variant, and in at least three other cases it has been reported in trans with another missense variant. The highest frequency of this allele in the Genome Aggregation Database is 0.001337 in the European (non-Finnish) population (version 3.1.2). Computational evidence suggests the variant may impact the gene or gene product. Based on the available evidence, the c.1244T>C (p.Met415Thr) variant is classified as a variant of uncertain significance for POLR3-related leukodystrophy. -

Hypogonadotropic hypogonadism 7 with or without anosmia;C3280644:Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism;C4706676:Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.32

MetaRNN

Uncertain

0.59

D;D

MetaSVM

Uncertain

-0.23

MutationAssessor

Uncertain

2.1

M;.

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-2.9

D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.42

B;.

Vest4

0.98

MVP

0.78

MPC

1.1

ClinPred

0.13

GERP RS

5.8

Varity_R

0.71

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over