10-77986123-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_007055.4(POLR3A):c.2938A>G(p.Ile980Val) variant causes a missense change. The variant allele was found at a frequency of 0.00845 in 1,593,422 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0087 ( 99 hom. )

Consequence

POLR3A
NM_007055.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.85

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

odontoleukodystrophy
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
Wiedemann-Rautenstrauch syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
tremor-ataxia-central hypomyelination syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

POLR3A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0091528).

BP6

Variant 10-77986123-T-C is Benign according to our data. Variant chr10-77986123-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00574 (875/152326) while in subpopulation NFE AF = 0.0093 (633/68036). AF 95% confidence interval is 0.0087. There are 4 homozygotes in GnomAd4. There are 389 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3A	NM_007055.4 link	c.2938A>G	p.Ile980Val	missense_variant	Exon 22 of 31	ENST00000372371.8	NP_008986.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3A	ENST00000372371.8 link	c.2938A>G	p.Ile980Val	missense_variant	Exon 22 of 31	1	NM_007055.4	ENSP00000361446.3

Frequencies

GnomAD3 genomes

AF:

0.00575

AC:

875

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00212

Gnomad AMI

AF:

0.0209

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00932

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00620

AC:

1558

AN:

251438

AF XY:

0.00600

show subpopulations

Gnomad AFR exome

AF:

0.00197

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.0177

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00226

Gnomad NFE exome

AF:

0.0103

Gnomad OTH exome

AF:

0.00570

GnomAD4 exome

AF:

0.00874

AC:

12595

AN:

1441096

Hom.:

Cov.:

AF XY:

0.00843

AC XY:

6060

AN XY:

718598

show subpopulations

African (AFR)

AF:

0.00136

AC:

AN:

33066

American (AMR)

AF:

0.00177

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0182

AC:

474

AN:

25988

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39604

South Asian (SAS)

AF:

0.00126

AC:

108

AN:

85842

European-Finnish (FIN)

AF:

0.00230

AC:

123

AN:

53414

Middle Eastern (MID)

AF:

0.000699

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.0104

AC:

11327

AN:

1093068

Other (OTH)

AF:

0.00727

AC:

434

AN:

59684

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

588

1175

1763

2350

2938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

422

844

1266

1688

2110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00574

AC:

875

AN:

152326

Hom.:

Cov.:

AF XY:

0.00522

AC XY:

389

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

41572

American (AMR)

AF:

0.00190

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00166

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00217

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00930

AC:

633

AN:

68036

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

127

170

212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00874

Hom.:

Bravo

AF:

0.00578

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0103

AC:

ExAC

AF:

0.00636

AC:

772

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00954

EpiControl

AF:

0.00853

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jun 27, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

POLR3A: BS1, BS2 -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 15, 2019

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Neonatal pseudo-hydrocephalic progeroid syndrome;C4706676:Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome

Benign:1

Apr 27, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

POLR3A-related disorder

Benign:1

Apr 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

-0.51

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-0.11

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0092

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.72

PhyloP100

5.9

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.61

REVEL

Benign

0.098

Sift

Benign

0.24

Sift4G

Benign

0.28

Polyphen

0.0010

Vest4

0.44

MVP

0.56

MPC

0.29

ClinPred

0.015

GERP RS

5.3

Varity_R

0.094

gMVP

0.36

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over