rs3212989

Variant names:

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

Frequency

Genomes: 𝑓 0.020 ( 76 hom., cov: 31)

Exomes 𝑓: 0.0024 ( 91 hom. )

Consequence

POLR1G
NM_012099.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:5

Conservation

PhyloP100: -2.04

Publications

12 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=0.0020589828).

BP6

Variant 19-45408812-A-G is Benign according to our data. Variant chr19-45408812-A-G is described in ClinVar as Benign. ClinVar VariationId is 235480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
POLR1G	NM_012099.3 link	c.844A>G	p.Thr282Ala	missense_variant	Exon 3 of 3	ENST00000309424.8	NP_036231.1
ERCC1	NM_001983.4 link	c.*863T>C		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.844A>G	p.Thr282Ala	missense_variant	Exon 3 of 3	1	NM_012099.3	ENSP00000310966.3
ERCC1	ENST00000300853.8 link	c.*863T>C		3_prime_UTR_variant	Exon 10 of 10	1	NM_001983.4	ENSP00000300853.3

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

GnomAD2 exomes

AF:

0.00558

AC:

1387

AN:

248640

AF XY:

0.00437

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 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

African (AFR)

AF:

0.0729

AC:

2441

AN:

33478

American (AMR)

AF:

0.00402

AC:

180

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00991

AC:

259

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000185

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00572

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000245

AC:

272

AN:

1112008

Other (OTH)

AF:

0.00530

AC:

320

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

226

452

677

903

1129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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:

0.0196

AC:

2989

AN:

152194

Hom.:

Cov.:

AF XY:

0.0192

AC XY:

1430

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0675

AC:

2800

AN:

41498

American (AMR)

AF:

0.00667

AC:

102

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00953

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68006

Other (OTH)

AF:

0.0123

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

149

298

447

596

745

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.00860

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: Benign

Submissions summary: Pathogenic:1Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:2

Oct 28, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Pathogenic

Review Status:flagged submission

Collection Method:clinical testing

- -

Jul 10, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 15, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Oct 28, 2020

H3Africa Consortium

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

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

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

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

Jan 20, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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;.

PhyloP100

-2.0

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

Mutation Taster

=98/2

disease causing (ClinVar)

(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