rs3212986

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

Publications

477 publications found

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 Gene-Disease associations (from GenCC):

cerebrooculofacioskeletal syndrome 4
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
Cockayne syndrome type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
COFS syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ERCC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
POLR1G	NM_012099.3 link	c.1510C>A	p.Gln504Lys	missense_variant	Exon 3 of 3	ENST00000309424.8	NP_036231.1
ERCC1	NM_001983.4 link	c.*197G>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000300853.8	NP_001974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR1G	ENST00000309424.8 link	c.1510C>A	p.Gln504Lys	missense_variant	Exon 3 of 3	1	NM_012099.3	ENSP00000310966.3
ERCC1	ENST00000300853.8 link	c.*197G>T		3_prime_UTR_variant	Exon 10 of 10	1	NM_001983.4	ENSP00000300853.3

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

GnomAD2 exomes

AF:

0.289

AC:

67411

AN:

233160

AF XY:

0.284

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 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

African (AFR)

AF:

0.285

AC:

9524

AN:

33360

American (AMR)

AF:

0.407

AC:

17798

AN:

43724

Ashkenazi Jewish (ASJ)

AF:

0.245

AC:

6367

AN:

26026

East Asian (EAS)

AF:

0.270

AC:

10681

AN:

39540

South Asian (SAS)

AF:

0.303

AC:

25954

AN:

85720

European-Finnish (FIN)

AF:

0.221

AC:

11230

AN:

50728

Middle Eastern (MID)

AF:

0.253

AC:

1393

AN:

5516

European-Non Finnish (NFE)

AF:

0.246

AC:

272911

AN:

1109086

Other (OTH)

AF:

0.266

AC:

15995

AN:

60068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

16473

32946

49420

65893

82366

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9494

18988

28482

37976

47470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.272

AC:

41356

AN:

152028

Hom.:

5761

Cov.:

AF XY:

0.273

AC XY:

20304

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.293

AC:

12163

AN:

41454

American (AMR)

AF:

0.352

AC:

5362

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.245

AC:

849

AN:

3470

East Asian (EAS)

AF:

0.310

AC:

1599

AN:

5162

South Asian (SAS)

AF:

0.303

AC:

1461

AN:

4824

European-Finnish (FIN)

AF:

0.225

AC:

2376

AN:

10578

Middle Eastern (MID)

AF:

0.216

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.244

AC:

16590

AN:

67978

Other (OTH)

AF:

0.271

AC:

571

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1559

3118

4677

6236

7795

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

422

844

1266

1688

2110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.258

Hom.:

18608

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 10952103, 18635523, 23203453) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.

PhyloP100

-1.5

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

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over