rs1046282

Positions:

• chr19-45407414-A-G

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC1	NM_001983.4	c.*2261T>C		3_prime_UTR_variant	10/10	ENST00000300853.8
POLR1G	NM_012099.3	c.164+179A>G		intron_variant		ENST00000309424.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC1	ENST00000300853.8	c.*2261T>C		3_prime_UTR_variant	10/10	1	NM_001983.4	P1
POLR1G	ENST00000309424.8	c.164+179A>G		intron_variant		1	NM_012099.3	P4

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

Gnomad4 AFR exome AF: 0.360

Gnomad4 AMR exome AF: 0.382

Gnomad4 ASJ exome AF: 0.241

Gnomad4 EAS exome AF: 0.244

Gnomad4 SAS exome AF: 0.302

Gnomad4 FIN exome AF: 0.220

Gnomad4 NFE exome AF: 0.246

Gnomad4 OTH exome AF: 0.273

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

Gnomad4 AFR AF: 0.381

Gnomad4 AMR AF: 0.368

Gnomad4 ASJ AF: 0.249

Gnomad4 EAS AF: 0.310

Gnomad4 SAS AF: 0.305

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.249

Gnomad4 OTH AF: 0.293

Alfa AF: 0.288 Hom.: 1177

Bravo AF: 0.317

Asia WGS AF: 0.329 AC: 1148 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.4
DANN	Benign	0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs1046282; hg19: chr19-45910672;