12-106444495-C-T

Position:

chr12-106444495-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP2PP3_StrongPP5_Very_Strong

The NM_018082.6(POLR3B):c.1988C>T(p.Thr663Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,613,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

POLR3B
NM_018082.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.83

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 Pathogenic. Variant got 13 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), POLR3B. . Gene score misZ 3.1978 (greater than the threshold 3.09). Trascript score misZ 3.4842 (greater than threshold 3.09). GenCC has associacion of gene with 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.947

PP5

Variant 12-106444495-C-T is Pathogenic according to our data. Variant chr12-106444495-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 242494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3B	NM_018082.6 linkuse as main transcript	c.1988C>T	p.Thr663Ile	missense_variant	19/28	ENST00000228347.9	NP_060552.4	Q9NW08-1Q7Z3R8
POLR3B	NM_001160708.2 linkuse as main transcript	c.1814C>T	p.Thr605Ile	missense_variant	19/28		NP_001154180.1	Q9NW08-2
POLR3B	XM_017019621.3 linkuse as main transcript	c.1988C>T	p.Thr663Ile	missense_variant	19/26		XP_016875110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR3B	ENST00000228347.9 linkuse as main transcript	c.1988C>T	p.Thr663Ile	missense_variant	19/28	1	NM_018082.6	ENSP00000228347.4		Q9NW08-1
POLR3B	ENST00000539066.5 linkuse as main transcript	c.1814C>T	p.Thr605Ile	missense_variant	19/28	2		ENSP00000445721.1		Q9NW08-2

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000955

AC:

AN:

251394

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000595

AC:

AN:

1461716

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000206

Gnomad4 NFE exome

AF:

0.0000648

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000160

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2023	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: 26204956, 25326637) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -

not specified

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Sep 22, 2022

- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

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

Feb 28, 2022

The p.Thr663Ile variant in POLR3B has been reported in 2 individuals with 4H leukodystrophy (PMID: 26204956, 25326637) and has been identified in 0.02% (21/129082) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs755312623). 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. Of the 2 affected individuals, both were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Thr663Ile variant is pathogenic (VariationID: 31166; PMID: 26204956, 25326637). This variant has also been reported in ClinVar (Variation ID#: 242494) and has been interpreted as likely pathogenic by Institute of Medical Genetics and Applied Genomics (University Hospital T√ºbingen). 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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive 4H leukodystrophy. ACMG/AMP Criteria applied: PP3, PP2, PM3_strong (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

0.066

MutationAssessor

Pathogenic

2.9

M;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.070

T;T

Polyphen

0.89

P;.

Vest4

0.97

MVP

0.79

MPC

1.0

ClinPred

0.96

GERP RS

4.4

Varity_R

0.91

gMVP

0.85

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