16-13935495-C-G

Position:

chr16-13935495-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

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. 15/21 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:4O:1

Conservation

PhyloP100: 2.06

Variant links:

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 links:

ERCC4 (HGNC:):

ERCC4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity XPF_HUMAN

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 id is 134153.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=6, not_provided=1}.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC4	NM_005236.3 linkuse as main transcript	c.1563C>G	p.Ser521Arg	missense_variant	8/11	ENST00000311895.8	NP_005227.1	Q92889-1A0A1W1GSK9
ERCC4	XM_011522424.4 linkuse as main transcript	c.1701C>G	p.Ser567Arg	missense_variant	9/12		XP_011520726.1	A0A804HKF9
ERCC4	XM_047433774.1 linkuse as main transcript	c.774C>G	p.Ser258Arg	missense_variant	5/8		XP_047289730.1
ERCC4	XM_011522427.2 linkuse as main transcript	c.213C>G	p.Ser71Arg	missense_variant	3/6		XP_011520729.1	B4DXD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8 linkuse as main transcript	c.1563C>G	p.Ser521Arg	missense_variant	8/11	1	NM_005236.3	ENSP00000310520.7		Q92889-1

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

154

AN:

152096

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000880

AC:

221

AN:

251214

Hom.:

AF XY:

0.000876

AC XY:

119

AN XY:

135866

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.00121

AC XY:

883

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00148

Gnomad4 OTH exome

AF:

0.00154

GnomAD4 genome

AF:

0.00101

AC:

154

AN:

152214

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00451

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00107

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00112

Hom.:

Bravo

AF:

0.00117

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000700

AC:

EpiCase

AF:

0.00185

EpiControl

AF:

0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 29, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ENSG00000262732: BS2; ERCC4: BP4, BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified

Uncertain:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 15, 2020	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

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 13, 2019

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

Xeroderma pigmentosum, group F

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

- -

Xeroderma pigmentosum

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Jan 06, 2022

- -

ERCC4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 20, 2022

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.16

Eigen

Benign

0.15

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.67

M_CAP

Benign

0.015

MetaRNN

Benign

0.0078

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.5

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.0

REVEL

Benign

0.11

Sift

Benign

0.40

Sift4G

Benign

0.61

Polyphen

0.66

Vest4

0.41

MutPred

0.35

Loss of phosphorylation at S521 (P = 0.0047);

MVP

0.88

MPC

0.22

ClinPred

0.021

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.094

gMVP

0.45

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over