chr19-45417538-C-T

Variant names:

• chr19-45417538-C-T
• rs3212964
• NM_001983.4:c.526-641G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001983.4(ERCC1):​c.526-641G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 151,848 control chromosomes in the GnomAD database, including 2,807 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 0.18 (2807 hom., cov: 31)
• Consequence: ERCC1 NM_001983.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.91
• Publications: 29 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC1	NM_001983.4	c.526-641G>A		intron_variant	Intron 5 of 9	ENST00000300853.8	NP_001974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC1	ENST00000300853.8	c.526-641G>A		intron_variant	Intron 5 of 9	1	NM_001983.4	ENSP00000300853.3

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27449 AN: 151730 Hom.: 2796 Cov.: 31

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.178

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.181 AC: 27478 AN: 151848 Hom.: 2807 Cov.: 31 AF XY: 0.185 AC XY: 13744 AN XY: 74206

African (AFR) AF: 0.214 AC: 8847 AN: 41398

American (AMR) AF: 0.205 AC: 3126 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 489 AN: 3468

East Asian (EAS) AF: 0.425 AC: 2188 AN: 5144

South Asian (SAS) AF: 0.276 AC: 1327 AN: 4804

European-Finnish (FIN) AF: 0.145 AC: 1533 AN: 10548

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9423 AN: 67944

Other (OTH) AF: 0.176 AC: 371 AN: 2104

Alfa AF: 0.154 Hom.: 852

Bravo AF: 0.184

Asia WGS AF: 0.333 AC: 1157 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.3
DANN	Benign	0.33
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3212964; hg19: chr19-45920796;