dbSNP rs3212948: ERCC1:c.321+74C>T (chr19-45421104-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001983.4(ERCC1):c.321+74C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000639 in 1,095,540 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

ERCC1
NM_001983.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.386

Publications

46 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC1	NM_001983.4 link	c.321+74C>T		intron_variant	Intron 3 of 9	ENST00000300853.8	NP_001974.1	P07992-1A0A024R0Q6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC1	ENST00000300853.8 link	c.321+74C>T		intron_variant	Intron 3 of 9	1	NM_001983.4	ENSP00000300853.3		P07992-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000639

AC:

AN:

1095540

Hom.:

AF XY:

0.00000713

AC XY:

AN XY:

560720

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26656

American (AMR)

AF:

0.00

AC:

AN:

43374

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23762

East Asian (EAS)

AF:

0.00

AC:

AN:

37954

South Asian (SAS)

AF:

0.00

AC:

AN:

78146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51822

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3584

European-Non Finnish (NFE)

AF:

0.00000895

AC:

AN:

781864

Other (OTH)

AF:

0.00

AC:

AN:

48378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.3

(source)

DANN

Benign

0.95

PhyloP100

-0.39

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over