rs34588967

Positions:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM5PP2BP4_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. 13/20 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. R582H) has been classified as Benign.

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

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 -17 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-78009889-C-T is described in Lovd as [Likely_pathogenic].

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=0.0123824775).

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3A	NM_007055.4 linkuse as main transcript	c.1745G>T	p.Arg582Leu	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>T	p.Arg582Leu	missense_variant	13/31	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

GnomAD3 exomes

AF:

0.00858

AC:

2158

AN:

251472

Hom.:

AF XY:

0.00840

AC XY:

1142

AN XY:

135914

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 SAS exome

AF:

0.000523

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

Gnomad4 AFR exome

AF:

0.00254

Gnomad4 AMR exome

AF:

0.00686

Gnomad4 ASJ exome

AF:

0.0168

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000800

Gnomad4 FIN exome

AF:

0.00251

Gnomad4 NFE exome

AF:

0.0177

Gnomad4 OTH exome

AF:

0.0140

GnomAD4 genome

AF:

0.00966

AC:

1470

AN:

152188

Hom.:

Cov.:

AF XY:

0.00935

AC XY:

696

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.00279

Gnomad4 AMR

AF:

0.0123

Gnomad4 ASJ

AF:

0.0164

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00245

Gnomad4 NFE

AF:

0.0156

Gnomad4 OTH

AF:

0.00806

Alfa

AF:

0.0106

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	POLR3A: PM5, BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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). 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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 17, 2021

- -

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

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

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

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

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