rs3212939

Variant names:

• chr19-45423013-G-A
• rs3212939
• NM_001983.4:c.105+257C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001983.4(ERCC1):​c.105+257C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 152,140 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: 𝑓 0.019 (47 hom., cov: 31)
• Consequence: ERCC1 NM_001983.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.584
• Publications: 2 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=-0.9).
• BP6: Variant 19-45423013-G-A is Benign according to our data. Variant chr19-45423013-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1208315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0188 (2867/152140) while in subpopulation NFE AF = 0.0251 (1707/68016). AF 95% confidence interval is 0.0241. There are 47 homozygotes in GnomAd4. There are 1407 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 47 AR gene

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.105+257C>T		intron	N/A	NP_001974.1
	ERCC1	NM_001369408.1		c.105+257C>T		intron	N/A	NP_001356337.1
	ERCC1	NM_001369409.1		c.105+257C>T		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.105+257C>T		intron	N/A	ENSP00000300853.3
	ERCC1	ENST00000013807.9	TSL:1	c.105+257C>T		intron	N/A	ENSP00000013807.4
	ERCC1	ENST00000340192.11	TSL:1	c.105+257C>T		intron	N/A	ENSP00000345203.6

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2866 AN: 152022 Hom.: 47 Cov.: 31

Gnomad AFR AF: 0.00440

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.0556

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00457

Gnomad FIN AF: 0.0478

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0251

Gnomad OTH AF: 0.0158

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

GnomAD4 genome AF: 0.0188 AC: 2867 AN: 152140 Hom.: 47 Cov.: 31 AF XY: 0.0189 AC XY: 1407 AN XY: 74386

African (AFR) AF: 0.00438 AC: 182 AN: 41508

American (AMR) AF: 0.0143 AC: 219 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0556 AC: 193 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00478 AC: 23 AN: 4810

European-Finnish (FIN) AF: 0.0478 AC: 506 AN: 10576

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0251 AC: 1707 AN: 68016

Other (OTH) AF: 0.0156 AC: 33 AN: 2110

Alfa AF: 0.0209 Hom.: 7

Bravo AF: 0.0153

Asia WGS AF: 0.00289 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.2
DANN	Benign	0.79
PhyloP100		0.58
PromoterAI		-0.029	Neutral
Mutation Taster		=100/0	polymorphism

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: rs3212939; hg19: chr19-45926271;