19-45424352-A-G

Variant names:

• chr19-45424352-A-G
• rs3212930
• ENST00000589165.5:c.-537T>C

Variant summary

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

The ENST00000589165.5(ERCC1):​c.-537T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 152,432 control chromosomes in the GnomAD database, including 2,611 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 0.17 (2607 hom., cov: 32)
  • Exomes 𝑓: 0.19 (4 hom.)
• Consequence: ERCC1 ENST00000589165.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.325
• Publications: 13 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=-0.79).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000589165.5. 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_001369412.1		c.-7-971T>C		intron	N/A	NP_001356341.1
	ERCC1	NM_001369413.1		c.-7-971T>C		intron	N/A	NP_001356342.1
	ERCC1	NM_001369414.1		c.-7-971T>C		intron	N/A	NP_001356343.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC1	ENST00000589165.5	TSL:5	c.-537T>C		5_prime_UTR	Exon 1 of 10	ENSP00000468035.1
	ERCC1	ENST00000592083.5	TSL:5	c.-7-971T>C		intron	N/A	ENSP00000467183.1
	ERCC1	ENST00000423698.6	TSL:2	c.-7-971T>C		intron	N/A	ENSP00000394875.2

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26131 AN: 152086 Hom.: 2609 Cov.: 32

Gnomad AFR AF: 0.0950

Gnomad AMI AF: 0.341

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.0863

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.196

GnomAD4 exome AF: 0.193 AC: 44 AN: 228 Hom.: 4 Cov.: 0 AF XY: 0.154 AC XY: 20 AN XY: 130

African (AFR) AF: 0.333 AC: 2 AN: 6

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 4 AN: 14

East Asian (EAS) AF: 0.154 AC: 4 AN: 26

South Asian (SAS) AF: 0.00 AC: 0 AN: 6

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.203 AC: 30 AN: 148

Other (OTH) AF: 0.200 AC: 4 AN: 20

GnomAD4 genome AF: 0.172 AC: 26135 AN: 152204 Hom.: 2607 Cov.: 32 AF XY: 0.172 AC XY: 12792 AN XY: 74400

African (AFR) AF: 0.0948 AC: 3939 AN: 41554

American (AMR) AF: 0.259 AC: 3945 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 719 AN: 3470

East Asian (EAS) AF: 0.0863 AC: 447 AN: 5180

South Asian (SAS) AF: 0.190 AC: 913 AN: 4816

European-Finnish (FIN) AF: 0.129 AC: 1373 AN: 10612

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 14024 AN: 67998

Other (OTH) AF: 0.194 AC: 411 AN: 2114

Alfa AF: 0.175 Hom.: 324

Bravo AF: 0.177

Asia WGS AF: 0.122 AC: 428 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.1
DANN	Benign	0.80
PhyloP100		-0.33
PromoterAI		0.048	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs3212930; hg19: chr19-45927610;