19-45452414-A-G

Variant names:

• chr19-45452414-A-G
• rs10423854
• ENST00000423698.6:c.-8+26322T>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+26322T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.58 in 152,170 control chromosomes in the GnomAD database, including 28,587 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 0.58 (28587 hom., cov: 33)
• Consequence: ERCC1 ENST00000423698.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.571
• Publications: 4 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.858 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+26322T>C		intron_variant	Intron 1 of 8	2		ENSP00000394875.2

Frequencies

GnomAD3 genomes AF: 0.579 AC: 88110 AN: 152052 Hom.: 28531 Cov.: 33

Gnomad AFR AF: 0.866

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.707

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.418

Gnomad OTH AF: 0.540

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

GnomAD4 genome AF: 0.580 AC: 88226 AN: 152170 Hom.: 28587 Cov.: 33 AF XY: 0.583 AC XY: 43385 AN XY: 74382

African (AFR) AF: 0.866 AC: 35964 AN: 41544

American (AMR) AF: 0.633 AC: 9660 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 1471 AN: 3472

East Asian (EAS) AF: 0.707 AC: 3659 AN: 5174

South Asian (SAS) AF: 0.617 AC: 2977 AN: 4824

European-Finnish (FIN) AF: 0.413 AC: 4371 AN: 10586

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.418 AC: 28433 AN: 67992

Other (OTH) AF: 0.542 AC: 1143 AN: 2108

Alfa AF: 0.633 Hom.: 12484

Bravo AF: 0.608

Asia WGS AF: 0.665 AC: 2315 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.8
DANN	Benign	0.77
PhyloP100		0.57
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: rs10423854; hg19: chr19-45955672;