rs1800124

chr16-13948220-A-G

Variant summary

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

The NM_005236.3(ERCC4):c.2624A>G(p.Glu875Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,614,176 control chromosomes in the GnomAD database, including 255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (16 hom., cov: 32)
  • Exomes 𝑓: 0.016 (239 hom.)
• Consequence: ERCC4 NM_005236.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 8.70

Genes affected

ERCC4 (HGNC:3436): (ERCC excision repair 4, endonuclease catalytic subunit) The protein encoded by this gene forms a complex with ERCC1 and is involved in the 5' incision made during nucleotide excision repair. This complex is a structure specific DNA repair endonuclease that interacts with EME1. Defects in this gene are a cause of xeroderma pigmentosum complementation group F (XP-F), or xeroderma pigmentosum VI (XP6).[provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008160144).
• BP6: Variant 16-13948220-A-G is Benign according to our data. Variant chr16-13948220-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 129008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-13948220-A-G is described in Lovd as [Likely_benign]. Variant chr16-13948220-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0119 (1817/152290) while in subpopulation NFE AF= 0.0167 (1136/68020). AF 95% confidence interval is 0.0159. There are 16 homozygotes in gnomad4. There are 919 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC4	NM_005236.3	c.2624A>G	p.Glu875Gly	missense_variant	11/11	ENST00000311895.8
ERCC4	XM_011522424.4	c.2762A>G	p.Glu921Gly	missense_variant	12/12
ERCC4	XM_047433774.1	c.1835A>G	p.Glu612Gly	missense_variant	8/8
ERCC4	XM_011522427.2	c.1274A>G	p.Glu425Gly	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC4	ENST00000311895.8	c.2624A>G	p.Glu875Gly	missense_variant	11/11	1	NM_005236.3	P1
ERCC4	ENST00000682617.1	c.2762A>G	p.Glu921Gly	missense_variant	12/12
ERCC4	ENST00000389138.7	n.1901A>G		non_coding_transcript_exon_variant	6/6	2
ERCC4	ENST00000683962.1	c.*2318A>G		3_prime_UTR_variant, NMD_transcript_variant	12/12

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1815 AN: 152172 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00333

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0215

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0133 AC: 3345 AN: 251420 Hom.: 34 AF XY: 0.0136 AC XY: 1845 AN XY: 135876

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.0174

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00287

Gnomad FIN exome AF: 0.0208

Gnomad NFE exome AF: 0.0187

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.0157 AC: 22892 AN: 1461886 Hom.: 239 Cov.: 33 AF XY: 0.0156 AC XY: 11315 AN XY: 727248

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.0106

Gnomad4 ASJ exome AF: 0.0175

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00303

Gnomad4 FIN exome AF: 0.0206

Gnomad4 NFE exome AF: 0.0176

Gnomad4 OTH exome AF: 0.0147

GnomAD4 genome AF: 0.0119 AC: 1817 AN: 152290 Hom.: 16 Cov.: 32 AF XY: 0.0123 AC XY: 919 AN XY: 74458

Gnomad4 AFR AF: 0.00334

Gnomad4 AMR AF: 0.0117

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0215

Gnomad4 NFE AF: 0.0167

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0177 Hom.: 37

Bravo AF: 0.0118

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00432 AC: 19

ESP6500EA AF: 0.0174 AC: 150

ExAC AF: 0.0131 AC: 1591

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3 Other:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2019	This variant is associated with the following publications: (PMID: 28051113, 17419091, 24728327, 20061190, 22374244, 15886521, 10479728, 24465539, 18767034, 28690523, 19626602, 24704021, 24004570) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Xeroderma pigmentosum, group F Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Vantari Genetics

Dec 11, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.020	D
Polyphen		0.94	P
Vest4		0.18
MPC		0.28
ClinPred		0.026	T
GERP RS		6.2
Varity_R		0.55
gMVP		0.37

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: rs1800124; hg19: chr16-14042077; COSMIC: COSV61313162; COSMIC: COSV61313162;