10-78009889-C-T

Position:

chr10-78009889-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_007055.4(POLR3A):c.1745G>A(p.Arg582His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,614,074 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 15 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

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=0.011581957).

BP6

Variant 10-78009889-C-T is Benign according to our data. Variant chr10-78009889-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 377235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-78009889-C-T is described in Lovd as [Benign]. Variant chr10-78009889-C-T is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0064 (974/152190) while in subpopulation AFR AF= 0.0221 (916/41516). AF 95% confidence interval is 0.0209. There are 4 homozygotes in gnomad4. There are 457 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.1745G>A	p.Arg582His	missense_variant	13/31	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.1745G>A	p.Arg582His	missense_variant	13/31	1	NM_007055.4	ENSP00000361446.3		O14802

Frequencies

GnomAD3 genomes

AF:

0.00641

AC:

975

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0222

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00575

GnomAD3 exomes

AF:

0.00180

AC:

452

AN:

251472

Hom.:

AF XY:

0.00125

AC XY:

170

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.0232

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000671

AC:

981

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000589

AC XY:

428

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0234

Gnomad4 AMR exome

AF:

0.00152

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000360

Gnomad4 OTH exome

AF:

0.00129

GnomAD4 genome

AF:

0.00640

AC:

974

AN:

152190

Hom.:

Cov.:

AF XY:

0.00614

AC XY:

457

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.0221

Gnomad4 AMR

AF:

0.00262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.000698

Hom.:

Bravo

AF:

0.00670

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.00219

AC:

266

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	POLR3A: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2021	This variant is associated with the following publications: (PMID: 27535217, 27521716, 33713793, 26096995) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 01, 2016	- -

Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.18

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.048

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.51

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.57

REVEL

Benign

0.15

Sift

Uncertain

0.022

Sift4G

Uncertain

0.051

Polyphen

0.071

Vest4

0.75

MVP

0.71

MPC

0.43

ClinPred

0.025

GERP RS

3.9

Varity_R

0.053

gMVP

0.52

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