19-45459541-A-G

Variant names:

• chr19-45459541-A-G
• rs10415949
• ENST00000423698.6:c.-8+19195T>C

Variant summary

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

The ENST00000423698.6(ERCC1):​c.-8+19195T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 151,990 control chromosomes in the GnomAD database, including 8,680 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 0.33 (8680 hom., cov: 31)
• Consequence: ERCC1 ENST00000423698.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0530
• Publications: 15 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC1	ENST00000423698.6	c.-8+19195T>C		intron_variant	Intron 1 of 8	2		ENSP00000394875.2

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49363 AN: 151872 Hom.: 8655 Cov.: 31

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.412

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.308

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

GnomAD4 genome AF: 0.325 AC: 49427 AN: 151990 Hom.: 8680 Cov.: 31 AF XY: 0.330 AC XY: 24534 AN XY: 74300

African (AFR) AF: 0.448 AC: 18581 AN: 41444

American (AMR) AF: 0.342 AC: 5217 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 943 AN: 3470

East Asian (EAS) AF: 0.411 AC: 2118 AN: 5156

South Asian (SAS) AF: 0.366 AC: 1768 AN: 4826

European-Finnish (FIN) AF: 0.284 AC: 2997 AN: 10568

Middle Eastern (MID) AF: 0.322 AC: 94 AN: 292

European-Non Finnish (NFE) AF: 0.247 AC: 16805 AN: 67956

Other (OTH) AF: 0.304 AC: 641 AN: 2112

Alfa AF: 0.277 Hom.: 19816

Bravo AF: 0.332

Asia WGS AF: 0.338 AC: 1177 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.9
DANN	Benign	0.58
PhyloP100		-0.053
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10415949; hg19: chr19-45962799;