12-106357893-C-T

Position:

chr12-106357893-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4_StrongBP6_ModerateBS1

The NM_018082.6(POLR3B):c.14C>T(p.Ala5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,613,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

POLR3B
NM_018082.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.559

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 Benign. Variant got -9 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). The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. GenCC has associacion of the 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.0066670477).

BP6

Variant 12-106357893-C-T is Benign according to our data. Variant chr12-106357893-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 722734.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000998 (152/152326) while in subpopulation AFR AF= 0.00349 (145/41570). AF 95% confidence interval is 0.00302. There are 0 homozygotes in gnomad4. There are 77 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3B	NM_018082.6 link	c.14C>T	p.Ala5Val	missense_variant	1/28	ENST00000228347.9	NP_060552.4	Q9NW08-1Q7Z3R8
POLR3B	XM_017019621.3 link	c.14C>T	p.Ala5Val	missense_variant	1/26		XP_016875110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR3B	ENST00000228347.9 link	c.14C>T	p.Ala5Val	missense_variant	1/28	1	NM_018082.6	ENSP00000228347.4		Q9NW08-1

Frequencies

GnomAD3 genomes

AF:

0.000985

AC:

150

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00345

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000147

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000285

AC:

AN:

249456

Hom.:

AF XY:

0.000200

AC XY:

AN XY:

135168

show subpopulations

Gnomad AFR exome

AF:

0.00380

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000116

AC:

170

AN:

1461316

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

726934

show subpopulations

Gnomad4 AFR exome

AF:

0.00400

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000998

AC:

152

AN:

152326

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00349

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000259

Hom.:

Bravo

AF:

0.00124

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000354

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 04, 2023

- -

POLR3B-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.034

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.73

M_CAP

Benign

0.037

MetaRNN

Benign

0.0067

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.51

REVEL

Benign

0.090

Sift

Benign

0.24

Sift4G

Benign

0.46

Polyphen

0.32

Vest4

0.17

MVP

0.59

MPC

0.61

ClinPred

0.048

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.037

gMVP

0.36

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