rs1046282

Variant names:

• chr19-45407414-A-G
• rs1046282
• NM_001983.4:c.*2261T>C

Variant summary

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

The NM_001983.4(ERCC1):​c.*2261T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 582,008 control chromosomes in the GnomAD database, including 22,094 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 0.30 (7209 hom., cov: 32)
  • Exomes 𝑓: 0.26 (14885 hom.)
• Consequence: ERCC1 NM_001983.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.96
• Publications: 22 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]

POLR1G (HGNC:24219): (RNA polymerase I subunit G) Enables RNA binding activity. Predicted to be involved in transmembrane receptor protein tyrosine kinase signaling pathway. Predicted to act upstream of or within rRNA transcription. Located in cytosol; mitochondrion; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.376 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.*2261T>C		3_prime_UTR	Exon 10 of 10	NP_001974.1
	POLR1G	NM_012099.3	MANE Select	c.164+179A>G		intron	N/A	NP_036231.1
	ERCC1	NM_001369412.1		c.*2261T>C		3_prime_UTR	Exon 10 of 10	NP_001356341.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC1	ENST00000300853.8	TSL:1 MANE Select	c.*2261T>C		3_prime_UTR	Exon 10 of 10	ENSP00000300853.3
	POLR1G	ENST00000309424.8	TSL:1 MANE Select	c.164+179A>G		intron	N/A	ENSP00000310966.3
	POLR1G	ENST00000589804.1	TSL:1	c.170+179A>G		intron	N/A	ENSP00000465099.1

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45652 AN: 151986 Hom.: 7189 Cov.: 32

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.368

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.289

GnomAD4 exome AF: 0.257 AC: 110649 AN: 429902 Hom.: 14885 Cov.: 5 AF XY: 0.259 AC XY: 59151 AN XY: 228166

African (AFR) AF: 0.360 AC: 3580 AN: 9954

American (AMR) AF: 0.382 AC: 4658 AN: 12194

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 3286 AN: 13634

East Asian (EAS) AF: 0.244 AC: 6450 AN: 26480

South Asian (SAS) AF: 0.302 AC: 11509 AN: 38054

European-Finnish (FIN) AF: 0.220 AC: 6570 AN: 29834

Middle Eastern (MID) AF: 0.291 AC: 566 AN: 1946

European-Non Finnish (NFE) AF: 0.246 AC: 67187 AN: 272760

Other (OTH) AF: 0.273 AC: 6843 AN: 25046

GnomAD4 genome AF: 0.301 AC: 45722 AN: 152106 Hom.: 7209 Cov.: 32 AF XY: 0.300 AC XY: 22338 AN XY: 74370

African (AFR) AF: 0.381 AC: 15803 AN: 41484

American (AMR) AF: 0.368 AC: 5618 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 862 AN: 3468

East Asian (EAS) AF: 0.310 AC: 1601 AN: 5172

South Asian (SAS) AF: 0.305 AC: 1474 AN: 4826

European-Finnish (FIN) AF: 0.227 AC: 2402 AN: 10592

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.249 AC: 16952 AN: 67994

Other (OTH) AF: 0.293 AC: 618 AN: 2110

Alfa AF: 0.281 Hom.: 2025

Bravo AF: 0.317

Asia WGS AF: 0.329 AC: 1148 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.4
DANN	Benign	0.21
PhyloP100		-2.0
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: rs1046282; hg19: chr19-45910672;