rs4253231

Positions:

• chr10-49458762-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000124.4(ERCC6):​c.*53T>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 0.103 in 1,557,202 control chromosomes in the GnomAD database, including 9,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (888 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8535 hom.)
• Consequence: ERCC6 NM_000124.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.478

Genes affected

ERCC6 (HGNC:3438): (ERCC excision repair 6, chromatin remodeling factor) This gene encodes a DNA-binding protein that is important in transcription-coupled excision repair. The encoded protein has ATP-stimulated ATPase activity, interacts with several transcription and excision repair proteins, and may promote complex formation at DNA repair sites. Mutations in this gene are associated with Cockayne syndrome type B and cerebrooculofacioskeletal syndrome 1. Alternative splicing occurs between a splice site from exon 5 of this gene to the 3' splice site upstream of the open reading frame (ORF) of the adjacent gene, piggyback-derived-3 (GeneID:267004), which activates the alternative polyadenylation site downstream of the piggyback-derived-3 ORF. The resulting transcripts encode a fusion protein that shares sequence with the product of each individual gene. [provided by RefSeq, Mar 2016]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 10-49458762-A-G is Benign according to our data. Variant chr10-49458762-A-G is described in ClinVar as [Benign]. Clinvar id is 300031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC6	NM_000124.4	c.*53T>C		3_prime_UTR_variant	21/21	ENST00000355832.10
ERCC6	NM_001346440.2	c.*53T>C		3_prime_UTR_variant	21/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC6	ENST00000355832.10	c.*53T>C		3_prime_UTR_variant	21/21	1	NM_000124.4	P1
	ENST00000423283.1	n.235-13941A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15609 AN: 152140 Hom.: 882 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.0740

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.0701

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0855

Gnomad OTH AF: 0.0914

GnomAD4 exome AF: 0.103 AC: 144284 AN: 1404944 Hom.: 8535 Cov.: 24 AF XY: 0.104 AC XY: 73369 AN XY: 702242

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.171

Gnomad4 ASJ exome AF: 0.0838

Gnomad4 EAS exome AF: 0.186

Gnomad4 SAS exome AF: 0.191

Gnomad4 FIN exome AF: 0.0743

Gnomad4 NFE exome AF: 0.0912

Gnomad4 OTH exome AF: 0.108

GnomAD4 genome AF: 0.103 AC: 15637 AN: 152258 Hom.: 888 Cov.: 32 AF XY: 0.105 AC XY: 7819 AN XY: 74450

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.144

Gnomad4 ASJ AF: 0.0740

Gnomad4 EAS AF: 0.164

Gnomad4 SAS AF: 0.188

Gnomad4 FIN AF: 0.0701

Gnomad4 NFE AF: 0.0856

Gnomad4 OTH AF: 0.0975

Alfa AF: 0.0921 Hom.: 1203

Bravo AF: 0.108

Asia WGS AF: 0.192 AC: 666 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

COFS syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Cockayne syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Macular degeneration Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.8
DANN	Benign	0.84

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: rs4253231; hg19: chr10-50666808; COSMIC: COSV63388659; COSMIC: COSV63388659;