rs34917815

chr10-49459232-A-Cchr10-49459232-A-Gchr10-49459232-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_000124.4(ERCC6):c.4065T>G(p.Asp1355Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000453 in 1,613,900 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1355V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: ERCC6 NM_000124.4 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0420

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027449727).
• BP6: Variant 10-49459232-A-C is Benign according to our data. Variant chr10-49459232-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 255167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0023 (350/152214) while in subpopulation AFR AF= 0.00761 (316/41538). AF 95% confidence interval is 0.00692. There are 1 homozygotes in gnomad4. There are 160 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC6	NM_000124.4	c.4065T>G	p.Asp1355Glu	missense_variant, splice_region_variant	21/21	ENST00000355832.10
ERCC6	NM_001346440.2	c.4065T>G	p.Asp1355Glu	missense_variant, splice_region_variant	21/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC6	ENST00000355832.10	c.4065T>G	p.Asp1355Glu	missense_variant, splice_region_variant	21/21	1	NM_000124.4	P1
	ENST00000423283.1	n.235-13471A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 350 AN: 152096 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00763

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000666 AC: 166 AN: 249396 Hom.: 0 AF XY: 0.000504 AC XY: 68 AN XY: 135006

Gnomad AFR exome AF: 0.00673

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000170

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.000261 AC: 381 AN: 1461686 Hom.: 0 Cov.: 32 AF XY: 0.000220 AC XY: 160 AN XY: 727126

Gnomad4 AFR exome AF: 0.00615

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000764

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.00230 AC: 350 AN: 152214 Hom.: 1 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74428

Gnomad4 AFR AF: 0.00761

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000332 Hom.: 0

Bravo AF: 0.00253

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000700 AC: 85

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	3.3
Dann	Benign	0.96
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.84	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.39
Sift	Benign	0.20	T
Sift4G	Benign	0.42	T
Polyphen		0.88	P
Vest4		0.18
MutPred		0.12		Gain of helix (P = 0.0425);
MVP		0.38
MPC		0.15
ClinPred		0.0091	T
GERP RS		-11
Varity_R		0.047
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs34917815; hg19: chr10-50667278; COSMIC: COSV104674036; COSMIC: COSV104674036;