rs56214655

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_007055.4(POLR3A):c.1724A>T(p.Lys575Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,614,154 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 48 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 64 hom. )

Consequence

POLR3A
NM_007055.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.58

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:

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). The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. GenCC has associacion of the 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=0.008322179).

BP6

Variant 10-78009910-T-A is Benign according to our data. Variant chr10-78009910-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 301068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-78009910-T-A is described in Lovd as [Likely_pathogenic].

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3A	NM_007055.4 link	c.1724A>T	p.Lys575Met	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 link	c.1724A>T	p.Lys575Met	missense_variant	13/31	1	NM_007055.4	ENSP00000361446.3		O14802

Frequencies

GnomAD3 genomes

AF:

0.0149

AC:

2274

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0519

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00616

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.00402

AC:

1012

AN:

251468

Hom.:

AF XY:

0.00287

AC XY:

390

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0521

Gnomad AMR exome

AF:

0.00370

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00163

AC:

2388

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

1003

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0564

Gnomad4 AMR exome

AF:

0.00373

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000103

Gnomad4 OTH exome

AF:

0.00308

GnomAD4 genome

AF:

0.0149

AC:

2275

AN:

152266

Hom.:

Cov.:

AF XY:

0.0147

AC XY:

1091

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0517

Gnomad4 AMR

AF:

0.00615

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.00233

Hom.:

Bravo

AF:

0.0170

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0472

AC:

208

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00485

AC:

589

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

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	GeneDx	May 05, 2021	This variant is associated with the following publications: (PMID: 26096995) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 11, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

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 28, 2022

- -

POLR3A-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 11, 2019

This variant is classified as 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

0.26

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0083

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.6

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.43

Sift

Benign

0.19

Sift4G

Benign

0.090

Polyphen

0.71

Vest4

0.76

MVP

0.89

MPC

0.49

ClinPred

0.024

GERP RS

5.7

Varity_R

0.23

gMVP

0.78

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