19-45408812-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_012099.3(POLR1G):c.844A>G(p.Thr282Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,614,016 control chromosomes in the GnomAD database, including 167 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.020 ( 76 hom., cov: 31)

Exomes 𝑓: 0.0024 ( 91 hom. )

Consequence

POLR1G
NM_012099.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:5

Conservation

PhyloP100: -2.04

Variant links:

Genes affected

POLR1G (HGNC:24219): (RNA polymerase I subunit G) Enables RNA binding activity. Predicted to be involved in transmembrane receptor protein tyrosine kinase signaling pathway. Predicted to act upstream of or within rRNA transcription. Located in cytosol; mitochondrion; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]

POLR1G links:

ERCC1 (HGNC:3433): (ERCC excision repair 1, endonuclease non-catalytic subunit) The product of this gene functions in the nucleotide excision repair pathway, and is required for the repair of DNA lesions such as those induced by UV light or formed by electrophilic compounds including cisplatin. The encoded protein forms a heterodimer with the XPF endonuclease (also known as ERCC4), and the heterodimeric endonuclease catalyzes the 5' incision in the process of excising the DNA lesion. The heterodimeric endonuclease is also involved in recombinational DNA repair and in the repair of inter-strand crosslinks. Mutations in this gene result in cerebrooculofacioskeletal syndrome, and polymorphisms that alter expression of this gene may play a role in carcinogenesis. Multiple transcript variants encoding different isoforms have been found for this gene. The last exon of this gene overlaps with the CD3e molecule, epsilon associated protein gene on the opposite strand. [provided by RefSeq, Oct 2009]

ERCC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020589828).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLR1G	NM_012099.3 linkuse as main transcript	c.844A>G	p.Thr282Ala	missense_variant	3/3	ENST00000309424.8
ERCC1	NM_001983.4 linkuse as main transcript	c.*863T>C		3_prime_UTR_variant	10/10	ENST00000300853.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR1G	ENST00000309424.8 linkuse as main transcript	c.844A>G	p.Thr282Ala	missense_variant	3/3	1	NM_012099.3	P4	O15446-1
ERCC1	ENST00000300853.8 linkuse as main transcript	c.*863T>C		3_prime_UTR_variant	10/10	1	NM_001983.4	P1	P07992-1

Frequencies

GnomAD3 genomes

AF:

0.0196

AC:

2988

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00668

Gnomad ASJ

AF:

0.00953

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.00558

AC:

1387

AN:

248640

Hom.:

AF XY:

0.00437

AC XY:

589

AN XY:

134650

show subpopulations

Gnomad AFR exome

AF:

0.0672

Gnomad AMR exome

AF:

0.00344

Gnomad ASJ exome

AF:

0.0112

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000387

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00241

AC:

3521

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

1574

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.0729

Gnomad4 AMR exome

AF:

0.00402

Gnomad4 ASJ exome

AF:

0.00991

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000245

Gnomad4 OTH exome

AF:

0.00530

GnomAD4 genome

AF:

0.0196

AC:

2989

AN:

152194

Hom.:

Cov.:

AF XY:

0.0192

AC XY:

1430

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0675

Gnomad4 AMR

AF:

0.00667

Gnomad4 ASJ

AF:

0.00953

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.00889

Hom.:

Bravo

AF:

0.0222

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0672

AC:

296

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00661

AC:

803

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 28, 2015	- -

not specified

Benign:1

Benign, criteria provided, single submitter

research

H3Africa Consortium

Oct 28, 2020

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.082, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Cerebrooculofacioskeletal syndrome 4

Benign:1

Benign, no assertion criteria provided

curation

Reproductive Health Research and Development, BGI Genomics

Jan 06, 2020

NM_001297590.1:c.850A>G in ghe gene CD3EAP has an allele frequency of 0.067 in African subpopulation in the gnomAD database. A total of 52 homozygous occurrences are observed in the gnomAD database. This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1, BS2. -

ERCC1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 20, 2024

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

0.079

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.85

Cadd

Benign

0.10

Dann

Benign

0.65

DEOGEN2

Benign

0.018

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.46

T;T

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.14

N;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.8

N;.

REVEL

Benign

0.031

Sift

Benign

0.27

T;.

Sift4G

Benign

0.78

T;T

Polyphen

0.011

B;B

Vest4

0.021

MVP

0.067

MPC

0.17

ClinPred

0.0068

GERP RS

-6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.044

gMVP

0.053

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