rs4253047

chr10-49524093-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_000124.4(ERCC6):c.1337G>A(p.Gly446Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,612,966 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (9 hom., cov: 32)
  • Exomes 𝑓: 0.014 (154 hom.)
• Consequence: ERCC6 NM_000124.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.40

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]

PGBD3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059863925).
• BP6: Variant 10-49524093-C-T is Benign according to our data. Variant chr10-49524093-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 235642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49524093-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00982 (1494/152068) while in subpopulation NFE AF= 0.0151 (1027/67970). AF 95% confidence interval is 0.0143. There are 9 homozygotes in gnomad4. There are 728 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC6	NM_000124.4	c.1337G>A	p.Gly446Asp	missense_variant	5/21	ENST00000355832.10
ERCC6	NM_001277058.2	c.1337G>A	p.Gly446Asp	missense_variant	5/6	ENST00000447839.7
PGBD3	NM_170753.3	c.-68G>A		5_prime_UTR_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC6	ENST00000355832.10	c.1337G>A	p.Gly446Asp	missense_variant	5/21	1	NM_000124.4	P1
ERCC6	ENST00000447839.7	c.1337G>A	p.Gly446Asp	missense_variant	5/6	2	NM_001277058.2

Frequencies

GnomAD3 genomes AF: 0.00984 AC: 1495 AN: 151950 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00254

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00905

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0172

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00953 AC: 2367 AN: 248338 Hom.: 14 AF XY: 0.00962 AC XY: 1294 AN XY: 134490

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00662

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00287

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.00899

GnomAD4 exome AF: 0.0140 AC: 20401 AN: 1460898 Hom.: 154 Cov.: 31 AF XY: 0.0135 AC XY: 9806 AN XY: 726804

Gnomad4 AFR exome AF: 0.00242

Gnomad4 AMR exome AF: 0.00675

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00281

Gnomad4 FIN exome AF: 0.0178

Gnomad4 NFE exome AF: 0.0163

Gnomad4 OTH exome AF: 0.0108

GnomAD4 genome AF: 0.00982 AC: 1494 AN: 152068 Hom.: 9 Cov.: 32 AF XY: 0.00979 AC XY: 728 AN XY: 74348

Gnomad4 AFR AF: 0.00253

Gnomad4 AMR AF: 0.00903

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0172

Gnomad4 NFE AF: 0.0151

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0124 Hom.: 43

Bravo AF: 0.00870

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0141 AC: 121

ExAC AF: 0.00946 AC: 1148

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0133

EpiControl AF: 0.0143

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ERCC6: BP4, BS1, BS2; PGBD3: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

COFS syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cockayne syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Macular degeneration Benign:1

Likely 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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.059	T;.;.
Eigen	Benign	-0.053
Eigen_PC	Benign	-0.052
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.71	T;.;T
MetaRNN	Benign	0.0060	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.6	M;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.53	N;N;N
REVEL	Benign	0.058
Sift	Benign	0.61	T;D;D
Sift4G	Benign	0.54	T;T;T
Polyphen		0.48	P;.;.
Vest4		0.33
MVP		0.75
MPC		0.17
ClinPred		0.032	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.16

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: rs4253047; hg19: chr10-50732139; COSMIC: COSV63393791; COSMIC: COSV63393791;