2-127257337-C-T

Position:

• chr2-127257337-C-T

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.*259G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0376 in 522,666 control chromosomes in the GnomAD database, including 516 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (126 hom., cov: 32)
  • Exomes 𝑓: 0.039 (390 hom.)
• Consequence: ERCC3 NM_000122.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00300

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=-0.93).
• BP6: Variant 2-127257337-C-T is Benign according to our data. Variant chr2-127257337-C-T is described in ClinVar as [Benign]. Clinvar id is 331068.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 = 0.0339 (5157/152216) while in subpopulation NFE AF= 0.0478 (3252/67996). AF 95% confidence interval is 0.0465. There are 126 homozygotes in gnomad4. There are 2413 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 126 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC3	NM_000122.2	c.*259G>A		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.*259G>A		3_prime_UTR_variant	15/15	1	NM_000122.2	ENSP00000285398	P1

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5159 AN: 152098 Hom.: 126 Cov.: 32

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0339

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0163

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0478

Gnomad OTH AF: 0.0368

GnomAD4 exome AF: 0.0391 AC: 14479 AN: 370450 Hom.: 390 Cov.: 2 AF XY: 0.0387 AC XY: 7548 AN XY: 195078

Gnomad4 AFR exome AF: 0.0139

Gnomad4 AMR exome AF: 0.0316

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0164

Gnomad4 FIN exome AF: 0.0244

Gnomad4 NFE exome AF: 0.0476

Gnomad4 OTH exome AF: 0.0442

GnomAD4 genome AF: 0.0339 AC: 5157 AN: 152216 Hom.: 126 Cov.: 32 AF XY: 0.0324 AC XY: 2413 AN XY: 74430

Gnomad4 AFR AF: 0.0132

Gnomad4 AMR AF: 0.0339

Gnomad4 ASJ AF: 0.120

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0163

Gnomad4 FIN AF: 0.0218

Gnomad4 NFE AF: 0.0478

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.0449 Hom.: 84

Bravo AF: 0.0338

Asia WGS AF: 0.00953 AC: 34 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	- -
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 12, 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	-0.93
CADD	Benign	1.6
DANN	Benign	0.56
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: rs1803541; hg19: chr2-128014913;