chr2-127257567-G-A

Position:

• chr2-127257567-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000122.2(ERCC3):​c.*29C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,612,784 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (5 hom., cov: 32)
  • Exomes 𝑓: 0.011 (104 hom.)
• Consequence: ERCC3 NM_000122.2 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.347

Genes affected

ERCC3 (HGNC:3435): (ERCC excision repair 3, TFIIH core complex helicase subunit) This gene encodes an ATP-dependent DNA helicase that functions in nucleotide excision repair. The encoded protein is a subunit of basal transcription factor 2 (TFIIH) and, therefore, also functions in class II transcription. Mutations in this gene are associated with Xeroderma pigmentosum B, Cockayne's syndrome, and trichothiodystrophy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-127257567-G-A is Benign according to our data. Variant chr2-127257567-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 331072.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 = 0.00702 (1069/152274) while in subpopulation NFE AF= 0.012 (816/68022). AF 95% confidence interval is 0.0113. There are 5 homozygotes in gnomad4. There are 496 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC3	NM_000122.2	c.*29C>T		3_prime_UTR_variant	15/15	ENST00000285398.7	NP_000113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC3	ENST00000285398.7	c.*29C>T		3_prime_UTR_variant	15/15	1	NM_000122.2	ENSP00000285398	P1

Frequencies

GnomAD3 genomes AF: 0.00703 AC: 1069 AN: 152156 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00680 AC: 1709 AN: 251422 Hom.: 10 AF XY: 0.00674 AC XY: 916 AN XY: 135872

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00397

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.0110 AC: 16017 AN: 1460510 Hom.: 104 Cov.: 31 AF XY: 0.0106 AC XY: 7720 AN XY: 726560

Gnomad4 AFR exome AF: 0.00224

Gnomad4 AMR exome AF: 0.00338

Gnomad4 ASJ exome AF: 0.00356

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000603

Gnomad4 FIN exome AF: 0.00433

Gnomad4 NFE exome AF: 0.0134

Gnomad4 OTH exome AF: 0.00849

GnomAD4 genome AF: 0.00702 AC: 1069 AN: 152274 Hom.: 5 Cov.: 32 AF XY: 0.00666 AC XY: 496 AN XY: 74456

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.0105 Hom.: 7

Bravo AF: 0.00696

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	ERCC3: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Xeroderma pigmentosum group B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.4
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs4150523; hg19: chr2-128015143; COSMIC: COSV53430625; COSMIC: COSV53430625;