rs34588967

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1745G>T(p.Arg582Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,614,044 control chromosomes in the GnomAD database, including 190 homozygotes. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R582C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0097 ( 14 hom., cov: 32)

Exomes 𝑓: 0.015 ( 176 hom. )

Consequence

POLR3A
NM_007055.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.49

Publications

13 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=0.0123824775).

BP6

Variant 10-78009889-C-A is Benign according to our data. Variant chr10-78009889-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 130000.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 = 0.00966 (1470/152188) while in subpopulation NFE AF = 0.0156 (1058/68018). AF 95% confidence interval is 0.0148. There are 14 homozygotes in GnomAd4. There are 696 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3A	NM_007055.4 link	c.1745G>T	p.Arg582Leu	missense_variant	Exon 13 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.1745G>T	p.Arg582Leu	missense_variant	Exon 13 of 31	1	NM_007055.4	ENSP00000361446.3		O14802

Frequencies

GnomAD3 genomes

AF:

0.00967

AC:

1470

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00280

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.0123

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00245

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0156

Gnomad OTH

AF:

0.00814

GnomAD2 exomes

AF:

0.00858

AC:

2158

AN:

251472

AF XY:

0.00840

show subpopulations

Gnomad AFR exome

AF:

0.00338

Gnomad AMR exome

AF:

0.00700

Gnomad ASJ exome

AF:

0.0152

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00189

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.00961

GnomAD4 exome

AF:

0.0147

AC:

21562

AN:

1461856

Hom.:

176

Cov.:

AF XY:

0.0142

AC XY:

10342

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00254

AC:

AN:

33478

American (AMR)

AF:

0.00686

AC:

307

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0168

AC:

439

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.000800

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00251

AC:

134

AN:

53420

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0177

AC:

19672

AN:

1111978

Other (OTH)

AF:

0.0140

AC:

844

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

1198

2396

3594

4792

5990

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00966

AC:

1470

AN:

152188

Hom.:

Cov.:

AF XY:

0.00935

AC XY:

696

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.00279

AC:

116

AN:

41514

American (AMR)

AF:

0.0123

AC:

188

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00245

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0156

AC:

1058

AN:

68018

Other (OTH)

AF:

0.00806

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

152

227

303

379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0133

Hom.:

Bravo

AF:

0.00986

TwinsUK

AF:

0.0194

AC:

ALSPAC

AF:

0.0218

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0165

AC:

142

ExAC

AF:

0.00785

AC:

953

EpiCase

AF:

0.0156

EpiControl

AF:

0.0143

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

May 10, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

POLR3A: PM5, BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

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

Benign:1

Dec 17, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.035

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.57

PhyloP100

2.5

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.14

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.013

Polyphen

0.15

Vest4

0.60

MVP

0.79

MPC

0.47

ClinPred

0.029

GERP RS

3.9

Varity_R

0.16

gMVP

0.68

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs34588967

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