rs3212986

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_012099.3(POLR1G):c.1510C>A(p.Gln504Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,605,796 control chromosomes in the GnomAD database, including 54,211 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.27 ( 5761 hom., cov: 31)

Exomes 𝑓: 0.26 ( 48450 hom. )

Consequence

POLR1G
NM_012099.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.51

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.0486794E-4).

BP6

Variant 19-45409478-C-A is Benign according to our data. Variant chr19-45409478-C-A is described in ClinVar as [Benign]. Clinvar id is 225987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR1G	NM_012099.3 linkuse as main transcript	c.1510C>A	p.Gln504Lys	missense_variant	3/3	ENST00000309424.8	NP_036231.1
ERCC1	NM_001983.4 linkuse as main transcript	c.*197G>T		3_prime_UTR_variant	10/10	ENST00000300853.8	NP_001974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR1G	ENST00000309424.8 linkuse as main transcript	c.1510C>A	p.Gln504Lys	missense_variant	3/3	1	NM_012099.3	ENSP00000310966	P4	O15446-1
ERCC1	ENST00000300853.8 linkuse as main transcript	c.*197G>T		3_prime_UTR_variant	10/10	1	NM_001983.4	ENSP00000300853	P1	P07992-1

Frequencies

GnomAD3 genomes

AF:

0.272

AC:

41313

AN:

151910

Hom.:

5750

Cov.:

show subpopulations

Gnomad AFR

AF:

0.294

Gnomad AMI

AF:

0.354

Gnomad AMR

AF:

0.351

Gnomad ASJ

AF:

0.245

Gnomad EAS

AF:

0.309

Gnomad SAS

AF:

0.303

Gnomad FIN

AF:

0.225

Gnomad MID

AF:

0.213

Gnomad NFE

AF:

0.244

Gnomad OTH

AF:

0.267

GnomAD3 exomes

AF:

0.289

AC:

67411

AN:

233160

Hom.:

9838

AF XY:

0.284

AC XY:

36050

AN XY:

127022

show subpopulations

Gnomad AFR exome

AF:

0.307

Gnomad AMR exome

AF:

0.419

Gnomad ASJ exome

AF:

0.257

Gnomad EAS exome

AF:

0.322

Gnomad SAS exome

AF:

0.304

Gnomad FIN exome

AF:

0.225

Gnomad NFE exome

AF:

0.251

Gnomad OTH exome

AF:

0.269

GnomAD4 exome

AF:

0.256

AC:

371853

AN:

1453768

Hom.:

48450

Cov.:

AF XY:

0.256

AC XY:

184992

AN XY:

722782

show subpopulations

Gnomad4 AFR exome

AF:

0.285

Gnomad4 AMR exome

AF:

0.407

Gnomad4 ASJ exome

AF:

0.245

Gnomad4 EAS exome

AF:

0.270

Gnomad4 SAS exome

AF:

0.303

Gnomad4 FIN exome

AF:

0.221

Gnomad4 NFE exome

AF:

0.246

Gnomad4 OTH exome

AF:

0.266

GnomAD4 genome

AF:

0.272

AC:

41356

AN:

152028

Hom.:

5761

Cov.:

AF XY:

0.273

AC XY:

20304

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.293

Gnomad4 AMR

AF:

0.352

Gnomad4 ASJ

AF:

0.245

Gnomad4 EAS

AF:

0.310

Gnomad4 SAS

AF:

0.303

Gnomad4 FIN

AF:

0.225

Gnomad4 NFE

AF:

0.244

Gnomad4 OTH

AF:

0.271

Alfa

AF:

0.254

Hom.:

11489

Bravo

AF:

0.284

TwinsUK

AF:

0.260

AC:

965

ALSPAC

AF:

0.249

AC:

961

ESP6500AA

AF:

0.291

AC:

1274

ESP6500EA

AF:

0.246

AC:

2109

ExAC

AF:

0.271

AC:

32582

Asia WGS

AF:

0.315

AC:

1096

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	This variant is associated with the following publications: (PMID: 10952103, 18635523, 23203453) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.0080

DANN

Benign

0.53

DEOGEN2

Benign

0.0031

T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0092

LIST_S2

Benign

0.26

T;T

MetaRNN

Benign

0.00060

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-1.6

N;.

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.32

PROVEAN

Benign

1.4

N;.

REVEL

Benign

0.028

Sift

Benign

1.0

T;.

Sift4G

Benign

0.33

T;T

Polyphen

0.0

B;B

Vest4

0.058

MPC

0.19

ClinPred

0.0026

GERP RS

2.7

Varity_R

0.045

gMVP

0.043

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