19-45419065-G-T

Variant names:

• chr19-45419065-G-T
• rs3212961
• NM_001983.4:c.525+33C>A

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.525+33C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,450,612 control chromosomes in the GnomAD database, including 21,052 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2913 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18139 hom.)
• Consequence: ERCC1 NM_001983.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.10
• Publications: 59 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=-0.87).
• BP6: Variant 19-45419065-G-T is Benign according to our data. Variant chr19-45419065-G-T is described in ClinVar as Benign. ClinVar VariationId is 1228638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC1	NM_001983.4	c.525+33C>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.525+33C>A		intron_variant	Intron 5 of 9	1	NM_001983.4	ENSP00000300853.3

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27587 AN: 151978 Hom.: 2908 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.457

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.183

GnomAD2 exomes AF: 0.200 AC: 31708 AN: 158598 AF XY: 0.199

Gnomad AFR exome AF: 0.239

Gnomad AMR exome AF: 0.259

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.447

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.152 AC: 196985 AN: 1298518 Hom.: 18139 Cov.: 19 AF XY: 0.154 AC XY: 99761 AN XY: 645860

African (AFR) AF: 0.235 AC: 6995 AN: 29726

American (AMR) AF: 0.250 AC: 8951 AN: 35788

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 3214 AN: 24532

East Asian (EAS) AF: 0.473 AC: 16785 AN: 35502

South Asian (SAS) AF: 0.249 AC: 19281 AN: 77352

European-Finnish (FIN) AF: 0.148 AC: 7233 AN: 48710

Middle Eastern (MID) AF: 0.146 AC: 802 AN: 5502

European-Non Finnish (NFE) AF: 0.126 AC: 124771 AN: 986750

Other (OTH) AF: 0.164 AC: 8953 AN: 54656

GnomAD4 genome AF: 0.182 AC: 27613 AN: 152094 Hom.: 2913 Cov.: 32 AF XY: 0.186 AC XY: 13824 AN XY: 74348

African (AFR) AF: 0.235 AC: 9727 AN: 41462

American (AMR) AF: 0.200 AC: 3052 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 442 AN: 3472

East Asian (EAS) AF: 0.457 AC: 2358 AN: 5164

South Asian (SAS) AF: 0.264 AC: 1272 AN: 4826

European-Finnish (FIN) AF: 0.135 AC: 1434 AN: 10584

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.129 AC: 8781 AN: 68002

Other (OTH) AF: 0.181 AC: 383 AN: 2112

Alfa AF: 0.121 Hom.: 714

Bravo AF: 0.186

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	-0.87
CADD	Benign	0.041
DANN	Benign	0.49
PhyloP100		-2.1
PromoterAI		0.038	Neutral
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: rs3212961; hg19: chr19-45922323; COSMIC: COSV50004804; COSMIC: COSV50004804;