dbSNP rs3212930: ERCC1:c.-537T>C (chr19-45424352-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000589165.5(ERCC1):c.-537T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 152,432 control chromosomes in the GnomAD database, including 2,611 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.17 ( 2607 hom., cov: 32)

Exomes 𝑓: 0.19 ( 4 hom. )

Consequence

ERCC1
ENST00000589165.5 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.325

Publications

13 publications found

Variant links:

Genes affected

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
ERCC1	NM_001369412.1 link	c.-7-971T>C	intron_variant	Intron 1 of 9	NP_001356341.1
ERCC1	NM_001369413.1 link	c.-7-971T>C	intron_variant	Intron 2 of 10	NP_001356342.1
ERCC1	NM_001369414.1 link	c.-7-971T>C	intron_variant	Intron 2 of 10	NP_001356343.1
ERCC1	NM_001369417.1 link	c.-7-971T>C	intron_variant	Intron 2 of 9	NP_001356346.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
ERCC1	ENST00000589165.5 link	c.-537T>C	5_prime_UTR_variant	Exon 1 of 10	5	ENSP00000468035.1	P07992-1
ERCC1	ENST00000592083.5 link	c.-7-971T>C	intron_variant	Intron 2 of 8	5	ENSP00000467183.1	K7EP14
ERCC1	ENST00000423698.6 link	c.-7-971T>C	intron_variant	Intron 1 of 8	2	ENSP00000394875.2	P07992-4
ERCC1	ENST00000589214.1 link	c.-7-971T>C	intron_variant	Intron 1 of 3	3	ENSP00000465524.1	K7EK97

Frequencies

GnomAD3 genomes

AF:

0.172

AC:

26131

AN:

152086

Hom.:

2609

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0950

Gnomad AMI

AF:

0.341

Gnomad AMR

AF:

0.258

Gnomad ASJ

AF:

0.207

Gnomad EAS

AF:

0.0863

Gnomad SAS

AF:

0.189

Gnomad FIN

AF:

0.129

Gnomad MID

AF:

0.174

Gnomad NFE

AF:

0.206

Gnomad OTH

AF:

0.196

GnomAD4 exome

AF:

0.193

AC:

AN:

228

Hom.:

Cov.:

AF XY:

0.154

AC XY:

AN XY:

130

show subpopulations

African (AFR)

AF:

0.333

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.286

AC:

AN:

East Asian (EAS)

AF:

0.154

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.203

AC:

AN:

148

Other (OTH)

AF:

0.200

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.172

AC:

26135

AN:

152204

Hom.:

2607

Cov.:

AF XY:

0.172

AC XY:

12792

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.0948

AC:

3939

AN:

41554

American (AMR)

AF:

0.259

AC:

3945

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.207

AC:

719

AN:

3470

East Asian (EAS)

AF:

0.0863

AC:

447

AN:

5180

South Asian (SAS)

AF:

0.190

AC:

913

AN:

4816

European-Finnish (FIN)

AF:

0.129

AC:

1373

AN:

10612

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.206

AC:

14024

AN:

67998

Other (OTH)

AF:

0.194

AC:

411

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1088

2176

3264

4352

5440

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

274

548

822

1096

1370

<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:

0.175

Hom.:

324

Bravo

AF:

0.177

Asia WGS

AF:

0.122

AC:

428

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

6.1

(source)

DANN

Benign

0.80

PhyloP100

-0.33

PromoterAI

0.048

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Computational scores

Splicing

Publications

Other links and lift over