rs267608670

Positions:

chr10-78007761-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_007055.4(POLR3A):c.2015G>A(p.Gly672Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

POLR3A
NM_007055.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 7.57

Variant links:

Genes affected

POLR3A (HGNC:30074): (RNA polymerase III subunit A) The protein encoded by this gene is the catalytic component of RNA polymerase III, which synthesizes small RNAs. The encoded protein also acts as a sensor to detect foreign DNA and trigger an innate immune response. [provided by RefSeq, Aug 2011]

POLR3A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, POLR3A

PP3

MetaRNN computational evidence supports a deleterious effect, 0.967

PP5

Variant 10-78007761-C-T is Pathogenic according to our data. Variant chr10-78007761-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-78007761-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLR3A	NM_007055.4 linkuse as main transcript	c.2015G>A	p.Gly672Glu	missense_variant	15/31	ENST00000372371.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR3A	ENST00000372371.8 linkuse as main transcript	c.2015G>A	p.Gly672Glu	missense_variant	15/31	1	NM_007055.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251470

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461730

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727176

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:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.00000961

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome

Pathogenic:2Other:1

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 24, 2024	The p.Gly672Glu variant in POLR3A has been reported in 7 individuals with POLR3A-related disorders (PMID: 21855841, 33005949, 25339210), and has been identified in 0.006% (1/16256) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs267608670). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the 7 affected individuals, 2 of those were homozygotes, which increases the likelihood that the p.Gly672Glu variant is pathogenic (PMID: 21855841, 33005949). This variant has also been reported in ClinVar (Variation ID#: 31143) and has been interpreted as pathogenic by GeneReviews and OMIM. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Gly672Glu variant is uncertain. ACMG/AMP Criteria applied: PM3, PM2_supporting, PP3 (Richards 2015). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 09, 2011	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

POLR3A-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 01, 2024

The POLR3A c.2015G>A variant is predicted to result in the amino acid substitution p.Gly672Glu. This variant was reported both in the homozygous and compound heterozygous states in patients with hypomyelinating leukodystrophy (Bernard et al. 2011. PubMed ID: 21855841; Supplementary table e-1, Wolf et al. 2014. PubMed ID: 25339210). A recent study reviewed that this variant in the homozygous state did present typical neurological features of hypomyelinating leukodystrophy (4H leukodystrophy), although transgenic mouse models of this variant (in the homozygous state or in the compound heterozygous state with one null allele) did not demonstrate the phenotype of childhood-onset hypomyelinating leukodystrophy (Pelletier et al. 2021. PubMed ID: 33005949; Choquet et al. 2017. PubMed ID: 28407788). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. Based on the given information, this variant is classified as likely pathogenic. -

Pol III-related leukodystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 14, 2024

Variant summary: POLR3A c.2015G>A (p.Gly672Glu) results in a non-conservative amino acid change located in the RNA polymerase Rpb1, domain 3 (IPR007066) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251470 control chromosomes (gnomAD). c.2015G>A has been reported in the literature in multiple individuals affected with Tremor-ataxia with central hypomyelinating leukodystrophy (e.g. Bernard_2011). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 21855841). ClinVar contains an entry for this variant (Variation ID: 31143). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.79

MutationAssessor

Pathogenic

4.7

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.9

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.99

MVP

0.91

MPC

1.0

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.92

gMVP

0.96

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