10-77986123-T-C

Position:

chr10-77986123-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 12/20 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

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:

POLR3A (HGNC:):

POLR3A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), POLR3A. . Gene score misZ 2.3065 (greater than the threshold 3.09). Trascript score misZ 3.6654 (greater than threshold 3.09). GenCC has associacion of gene with 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.

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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3A	NM_007055.4 linkuse as main transcript	c.2938A>G	p.Ile980Val	missense_variant	22/31	ENST00000372371.8	NP_008986.2	O14802

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR3A	ENST00000372371.8 linkuse as main transcript	c.2938A>G	p.Ile980Val	missense_variant	22/31	1	NM_007055.4	ENSP00000361446.3		O14802

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

GnomAD3 exomes

AF:

0.00620

AC:

1558

AN:

251438

Hom.:

AF XY:

0.00600

AC XY:

816

AN XY:

135896

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 SAS exome

AF:

0.00121

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

Gnomad4 AFR exome

AF:

0.00136

Gnomad4 AMR exome

AF:

0.00177

Gnomad4 ASJ exome

AF:

0.0182

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00126

Gnomad4 FIN exome

AF:

0.00230

Gnomad4 NFE exome

AF:

0.0104

Gnomad4 OTH exome

AF:

0.00727

GnomAD4 genome

AF:

0.00574

AC:

875

AN:

152326

Hom.:

Cov.:

AF XY:

0.00522

AC XY:

389

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00212

Gnomad4 AMR

AF:

0.00190

Gnomad4 ASJ

AF:

0.0179

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00217

Gnomad4 NFE

AF:

0.00930

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00891

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

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 27, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	POLR3A: BS1, BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 15, 2019

- -

Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 27, 2022

- -

POLR3A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2019

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

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

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

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