19-45421104-G-C

Variant names:

• chr19-45421104-G-C
• rs3212948
• NM_001983.4:c.321+74C>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.321+74C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 1,245,936 control chromosomes in the GnomAD database, including 123,611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (25350 hom., cov: 31)
  • Exomes 𝑓: 0.40 (98261 hom.)
• Consequence: ERCC1 NM_001983.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.386
• Publications: 46 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=-0.92).
• BP6: Variant 19-45421104-G-C is Benign according to our data. Variant chr19-45421104-G-C is described in ClinVar as Benign. ClinVar VariationId is 1286343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.847 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001983.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC1	NM_001983.4	MANE Select	c.321+74C>G		intron	N/A	NP_001974.1
	ERCC1	NM_001369408.1		c.321+74C>G		intron	N/A	NP_001356337.1
	ERCC1	NM_001369409.1		c.321+74C>G		intron	N/A	NP_001356338.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC1	ENST00000300853.8	TSL:1 MANE Select	c.321+74C>G		intron	N/A	ENSP00000300853.3
	ERCC1	ENST00000013807.9	TSL:1	c.321+74C>G		intron	N/A	ENSP00000013807.4
	ERCC1	ENST00000340192.11	TSL:1	c.321+74C>G		intron	N/A	ENSP00000345203.6

Frequencies

GnomAD3 genomes AF: 0.532 AC: 80805 AN: 151942 Hom.: 25292 Cov.: 31

Gnomad AFR AF: 0.854

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.352

Gnomad EAS AF: 0.736

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.495

GnomAD4 exome AF: 0.402 AC: 439767 AN: 1093876 Hom.: 98261 AF XY: 0.402 AC XY: 225292 AN XY: 559928

African (AFR) AF: 0.868 AC: 23121 AN: 26644

American (AMR) AF: 0.677 AC: 29360 AN: 43356

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 8612 AN: 23750

East Asian (EAS) AF: 0.727 AC: 27584 AN: 37944

South Asian (SAS) AF: 0.519 AC: 40495 AN: 78092

European-Finnish (FIN) AF: 0.359 AC: 18593 AN: 51780

Middle Eastern (MID) AF: 0.419 AC: 1501 AN: 3582

European-Non Finnish (NFE) AF: 0.346 AC: 269634 AN: 780410

Other (OTH) AF: 0.432 AC: 20867 AN: 48318

GnomAD4 genome AF: 0.532 AC: 80925 AN: 152060 Hom.: 25350 Cov.: 31 AF XY: 0.535 AC XY: 39731 AN XY: 74310

African (AFR) AF: 0.854 AC: 35469 AN: 41512

American (AMR) AF: 0.581 AC: 8871 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 1217 AN: 3460

East Asian (EAS) AF: 0.736 AC: 3798 AN: 5162

South Asian (SAS) AF: 0.535 AC: 2576 AN: 4816

European-Finnish (FIN) AF: 0.357 AC: 3770 AN: 10572

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.348 AC: 23636 AN: 67944

Other (OTH) AF: 0.498 AC: 1052 AN: 2112

Alfa AF: 0.451 Hom.: 2302

Bravo AF: 0.562

Asia WGS AF: 0.664 AC: 2310 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.1
DANN	Benign	0.40
PhyloP100		-0.39
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: rs3212948; hg19: chr19-45924362; COSMIC: COSV50005954; COSMIC: COSV50005954;