rs267608682

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong

The NM_007055.4(POLR3A):c.3013C>T(p.Arg1005Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,838 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: not found (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:5O:1

Conservation

PhyloP100: 2.17

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 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the POLR3A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 2.3065 (below the threshold of 3.09). Trascript score misZ: 3.6654 (above the threshold of 3.09). GenCC associations: The gene is linked to leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome, Wiedemann-Rautenstrauch syndrome, hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome, tremor-ataxia-central hypomyelination syndrome, hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome, odontoleukodystrophy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.855

PP5

Variant 10-77985961-G-A is Pathogenic according to our data. Variant chr10-77985961-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-77985961-G-A is described in Lovd as [Likely_pathogenic]. Variant chr10-77985961-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3A	NM_007055.4 link	c.3013C>T	p.Arg1005Cys	missense_variant	Exon 23 of 31	ENST00000372371.8	NP_008986.2	O14802

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3A	ENST00000372371.8 link	c.3013C>T	p.Arg1005Cys	missense_variant	Exon 23 of 31	1	NM_007055.4	ENSP00000361446.3		O14802

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251424

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome

Pathogenic:2Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 11, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 01, 2022

MyeliNeuroGene Lab, McGill University Health Center Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Pathogenic:1

May 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1005 of the POLR3A protein (p.Arg1005Cys). This variant is present in population databases (rs267608682, gnomAD 0.006%). This missense change has been observed in individual(s) with hypomyelinating leukodystrophy (PMID: 21855841, 22036171, 23355746). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 31149). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLR3A protein function with a negative predictive value of 80%. This variant disrupts the p.Arg1005 amino acid residue in POLR3A. Other variant(s) that disrupt this residue have been observed in individuals with POLR3A-related conditions (PMID: 22451160), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Leukodystrophy

Pathogenic:1

Jan 24, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg1005Cys variant in POLR3A has been reported in 5 individual with hypomyelinating leukodystrophy (PMID:25339210, 34953043, 23355746, 21855841, 22036171), and has been identified in 0.009% (3/34590) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs267608682). 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. This variant has also been reported in ClinVar (Variation ID#: 31149) and has been interpreted as pathogenic by GeneReviews and OMIM and likely pathogenic by Invitae and DASA. Of the 5 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, which increases the likelihood that the p.Arg1005Cys variant is pathogenic (VariationID: 41245; PMID: 22036171). In vitro functional studies provide some evidence that the p.Arg1005Cys variant may impact protein function (PMID: 21855841). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Arg1005Cys variant is located in a region of POLR3A that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 21855841). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hypomyelinating leukodystrophy. ACMG/AMP Criteria applied: PM3, PS3_moderate, PM1_supporting, PM2_supporting (Richards 2015). -

Neonatal pseudo-hydrocephalic progeroid syndrome

Pathogenic:1

Feb 05, 2022

DASA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3013C>T;p.(Arg1005Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 31149; PMID: 23965854; 22451160; 22036171; 21855841) - PS4_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (RNA_pol_Rpb1_5) - PM1. The variant is present at low allele frequencies population databases (rs267608682 – gnomAD 0.0002386%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg1005Cys) was detected in trans with a pathogenic variant (PMID: 23965854; 22451160; 22036171; 21855841) - PM3. Pathogenic missense variant in this residue have been reported (ClinVar ID: 41246 - c.3014G>A;p.(Arg1005His)) - PM5. In summary, the currently available evidence indicates that the variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-0.56

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.62

Sift

Benign

0.13

Sift4G

Benign

0.10

Polyphen

0.92

Vest4

0.95

MutPred

0.63

Loss of helix (P = 0.028);

MVP

0.80

MPC

0.56

ClinPred

0.85

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.81

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