rs267608671

chr10-78000043-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP2 PP3 PP5_Very_Strong

The NM_007055.4(POLR3A):c.2554A>G(p.Met852Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,726 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 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: POLR3A NM_007055.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.67

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_007055.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, POLR3A
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 10-78000043-T-C is Pathogenic according to our data. Variant chr10-78000043-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-78000043-T-C is described in Lovd as [Pathogenic]. Variant chr10-78000043-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLR3A	NM_007055.4	c.2554A>G	p.Met852Val	missense_variant	19/31	ENST00000372371.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR3A	ENST00000372371.8	c.2554A>G	p.Met852Val	missense_variant	19/31	1	NM_007055.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152054 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251480 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461672 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727156

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152054 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74268

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 09, 2011	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Feb 14, 2023	The missense c.2554A>G (p.Met852Val) variant in POLR3A gene has been reported in compound heterozygous state in multiple individuals affected with Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism (Choquet K et al. 2019; Terao Y et al. 2012; Bernard G et al. 2011). The p.Met852Val variant has allele frequency 0.0008% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pthogenic / Likely Pathogenic. The amino acid change p.Met852Val in POLR3A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Met at position 852 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies are required to prove the pathogenicity for the variant, for these reasons, this variant has been classified as Likely Pthogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 21, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects POLR3A function (PMID: 30898877). 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. ClinVar contains an entry for this variant (Variation ID: 31145). This missense change has been observed in individuals with POLR3A-related conditions (PMID: 21855841, 25339210). This variant is present in population databases (rs267608671, gnomAD 0.006%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 852 of the POLR3A protein (p.Met852Val). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2016	The M852V variant in the POLR3A gene has been reported previously in several individuals with leukodystrophy, hypogonadotropic hypogonadism, and dental anomalies (Bernard et al., 2011; Terao et al., 2012; Daoud et al., 2013; Wolf et al., 2014). This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common variant in these populations. The M852V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The M852V variant is a strong candidate for a pathogenic variant. -

Leukodystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

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

Jan 24, 2024

The p.Met852Val variant in POLR3A has been reported in >10 individuals with POLR3A-related disorders (PMID: 21855841, 32600288, 23355746, 33190326, 29700822, 33652360, 22819058, 34296356, 25339210), and has been identified in 0.005% (1/18392) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP: rs267608671). 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: 31145) and has been interpreted as pathogenic by OMIM and GeneReviews and as likely pathogenic by GeneDx. Of the many affected individuals, 1 of those was a homozygote, 2 were compound heterozygotes that carried a reported likely pathogenic variant with unknown phase, and 2 were compound heterozygotes that carried variants of unknown significance in trans, which increases the likelihood that the p.Met852Val variant is pathogenic (Variation ID: 31146, 445922, 31147; PMID: 21855841, 33190326, 34296356). In vitro functional studies provide some evidence that the p.Met852Val variant may impact protein function (PMID: 30898877). 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.Met852Val 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, this variant meets criteria to be classified as pathogenic for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PM3_strong, PS3, PM1_supporting, PM2_supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.068	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.032	D
Polyphen		0.98	D
Vest4		0.97
MutPred		0.83		Gain of loop (P = 0.2045);
MVP		0.88
MPC		0.84
ClinPred		0.89	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.61		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs267608671; hg19: chr10-79759801;