16-13935495-C-G

Variant names:

• chr16-13935495-C-G
• rs41552412
• NM_005236.3:c.1563C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005236.3(ERCC4):​c.1563C>G​(p.Ser521Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,614,058 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: ERCC4 NM_005236.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:5 O:1
• Conservation: PhyloP100: 2.06
• Publications: 8 publications found

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]

ERCC4 Gene-Disease associations (from GenCC):

• xeroderma pigmentosum group F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, ClinGen
• Fanconi anemia complementation group Q

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• XFE progeroid syndrome

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum-Cockayne syndrome complex

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000262732 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007758498).
• BP6: Variant 16-13935495-C-G is Benign according to our data. Variant chr16-13935495-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134153.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00101 (154/152214) while in subpopulation AMR AF = 0.00451 (69/15290). AF 95% confidence interval is 0.00366. There are 3 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC4	NM_005236.3	c.1563C>G	p.Ser521Arg	missense_variant	Exon 8 of 11	ENST00000311895.8	NP_005227.1
ERCC4	XM_011522424.4	c.1701C>G	p.Ser567Arg	missense_variant	Exon 9 of 12		XP_011520726.1
ERCC4	XM_047433774.1	c.774C>G	p.Ser258Arg	missense_variant	Exon 5 of 8		XP_047289730.1
ERCC4	XM_011522427.2	c.213C>G	p.Ser71Arg	missense_variant	Exon 3 of 6		XP_011520729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8	c.1563C>G	p.Ser521Arg	missense_variant	Exon 8 of 11	1	NM_005236.3	ENSP00000310520.7

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152096 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000880 AC: 221 AN: 251214 AF XY: 0.000876

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00110

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00127 AC: 1852 AN: 1461844 Hom.: 1 Cov.: 32 AF XY: 0.00121 AC XY: 883 AN XY: 727226

African (AFR) AF: 0.000179 AC: 6 AN: 33476

American (AMR) AF: 0.00246 AC: 110 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00148 AC: 1641 AN: 1111966

Other (OTH) AF: 0.00154 AC: 93 AN: 60396

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152214 Hom.: 3 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74420

African (AFR) AF: 0.000169 AC: 7 AN: 41528

American (AMR) AF: 0.00451 AC: 69 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68018

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.00117

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000700 AC: 85

EpiCase AF: 0.00185

EpiControl AF: 0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ERCC4 p.Ser521Arg variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs41552412) as "With Uncertain significance allele", LOVD 3.0, and in ClinVar (classified as a VUS by Illumina, Invitae, Fulgent Genetics and ITMI; associated conditions of Xeroderma pigmnetosum, XFE progeroid syndrome, Cockayne syndrome, and Fanconi anemia complementation group Q).The variant was also identified in control databases in 240 of 282606 chromosomes (1 homozygous) at a frequency of 0.000849 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 81 of 35434 chromosomes (freq: 0.002286), Other in 13 of 7214 chromosomes (freq: 0.001802), European (non-Finnish) in 140 of 129056 chromosomes (freq: 0.001085) and African in 6 of 24864 chromosomes (freq: 0.000241), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) and South Asian populations. Bodian et al. sequenced whole genomes from 681 healthy individuals; the p.S521R variant was identified at an allele frequency of 0.0015 in the European population, and was not found in any other population frequency within the cohort (Bodian_2014_PMID: 24728327). The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder-like & MaxEntScan) predict the gain of a 5' splice site at c.1562 and c.1558, respectively. The p.Ser521 residue is conserved in mammals but not distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ENSG00000262732: BS2; ERCC4: BP4, BS2 -

Oct 29, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Dec 15, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the ERCC4 gene demonstrated a sequence change, c.1563C>G, in exon 8 that results in an amino acid change, p.Ser521Arg. This sequence change does not appear to have been previously described in patients with ERCC4-related disorders and has been described in the gnomAD database with a relatively high population frequency of 0.11% in non-Finnish European subpopulations (dbSNP rs41552412). The p.Ser521Arg change affects a moderately conserved amino acid residue located in a domain of the ERCC4 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ser521Arg substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ser521Arg change remains unknown at this time. -

Fanconi anemia complementation group Q Uncertain:1

Apr 13, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Xeroderma pigmentosum, group F Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Xeroderma pigmentosum, group F;C1970416:XFE progeroid syndrome;C3808988:Fanconi anemia complementation group Q Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Xeroderma pigmentosum Benign:1

Jan 06, 2022

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

ERCC4-related disorder Benign:1

Jul 20, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome Benign:1

Oct 01, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1, BP4_moderate c.1563C>G, located in exon 8 of the ERCC4 gene, is predicted to result in the substitution of Serine by Arginine at codon 521, p.(Ser521Arg). The variant allele was found in 80/35102 alleles (1 homozygote), with a filter allele frequency of 0.18% at 95% confidence, within the Admixed American population in the gnomAD v2.1.1 database (non-cancer data set) (BA1). The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0.11) suggests that it does not affect the protein function according Pejaver 2022 thresholds (PMID: 36413997) (BP4_moderate). To our knowledge, neither clinical data nor functional studies have been reported for this variant. It has only been reported in ClinVar (7x uncertain significance, 4x likely benign). Based on currently available information, c.1563C>G is classified as a benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.1
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.11
Sift	Benign	0.40	T
Sift4G	Benign	0.61	T
Polyphen		0.66	P
Vest4		0.41
MutPred		0.35		Loss of phosphorylation at S521 (P = 0.0047);
MVP		0.88
MPC		0.22
ClinPred		0.021	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.094
gMVP		0.45
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41552412; hg19: chr16-14029352; COSMIC: COSV104606309;