chr19-45420238-T-C

Variant names:

• chr19-45420238-T-C
• rs3212955
• NM_001983.4:c.425+86A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001983.4(ERCC1):​c.425+86A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 896,490 control chromosomes in the GnomAD database, including 29,466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5559 hom., cov: 31)
  • Exomes 𝑓: 0.25 (23907 hom.)
• Consequence: ERCC1 NM_001983.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.90
• Publications: 27 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-45420238-T-C is Benign according to our data. Variant chr19-45420238-T-C is described in ClinVar as Benign. ClinVar VariationId is 1286234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC1	NM_001983.4	c.425+86A>G		intron_variant	Intron 4 of 9	ENST00000300853.8	NP_001974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC1	ENST00000300853.8	c.425+86A>G		intron_variant	Intron 4 of 9	1	NM_001983.4	ENSP00000300853.3

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40354 AN: 151776 Hom.: 5552 Cov.: 31

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.262

GnomAD4 exome AF: 0.248 AC: 184732 AN: 744596 Hom.: 23907 AF XY: 0.247 AC XY: 96656 AN XY: 390682

African (AFR) AF: 0.278 AC: 5195 AN: 18680

American (AMR) AF: 0.402 AC: 14197 AN: 35310

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 5394 AN: 21274

East Asian (EAS) AF: 0.255 AC: 8395 AN: 32880

South Asian (SAS) AF: 0.265 AC: 17751 AN: 67080

European-Finnish (FIN) AF: 0.208 AC: 8985 AN: 43224

Middle Eastern (MID) AF: 0.239 AC: 1017 AN: 4252

European-Non Finnish (NFE) AF: 0.235 AC: 114240 AN: 485260

Other (OTH) AF: 0.261 AC: 9558 AN: 36636

GnomAD4 genome AF: 0.266 AC: 40387 AN: 151894 Hom.: 5559 Cov.: 31 AF XY: 0.267 AC XY: 19828 AN XY: 74262

African (AFR) AF: 0.283 AC: 11730 AN: 41398

American (AMR) AF: 0.355 AC: 5419 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 871 AN: 3468

East Asian (EAS) AF: 0.298 AC: 1533 AN: 5148

South Asian (SAS) AF: 0.270 AC: 1296 AN: 4808

European-Finnish (FIN) AF: 0.218 AC: 2309 AN: 10580

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16286 AN: 67918

Other (OTH) AF: 0.266 AC: 561 AN: 2106

Alfa AF: 0.264 Hom.: 2076

Bravo AF: 0.278

Asia WGS AF: 0.309 AC: 1078 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.095
DANN	Benign	0.69
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: rs3212955; hg19: chr19-45923496; COSMIC: COSV50004094; COSMIC: COSV50004094;