chr16-13920181-C-T

Position:

chr16-13920181-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005236.3(ERCC4):c.16C>T(p.Pro6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000612 in 1,605,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00062 ( 0 hom. )

Consequence

ERCC4
NM_005236.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:15O:1

Conservation

PhyloP100: -0.201

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.013627112).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC4	NM_005236.3 linkuse as main transcript	c.16C>T	p.Pro6Ser	missense_variant	1/11	ENST00000311895.8	NP_005227.1	Q92889-1A0A1W1GSK9
ERCC4	XM_011522424.4 linkuse as main transcript	c.16C>T	p.Pro6Ser	missense_variant	1/12		XP_011520726.1	A0A804HKF9
LOC105371093	XR_007064999.1 linkuse as main transcript	n.82+6344G>A		intron_variant
LOC105371093	XR_007065000.1 linkuse as main transcript	n.82+6344G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8 linkuse as main transcript	c.16C>T	p.Pro6Ser	missense_variant	1/11	1	NM_005236.3	ENSP00000310520.7		Q92889-1

Frequencies

GnomAD3 genomes

AF:

0.000532

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00104

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000458

AC:

111

AN:

242132

Hom.:

AF XY:

0.000423

AC XY:

AN XY:

132282

show subpopulations

Gnomad AFR exome

AF:

0.0000637

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000189

Gnomad NFE exome

AF:

0.000945

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000621

AC:

902

AN:

1453464

Hom.:

Cov.:

AF XY:

0.000607

AC XY:

439

AN XY:

723482

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000418

Gnomad4 NFE exome

AF:

0.000771

Gnomad4 OTH exome

AF:

0.000415

GnomAD4 genome

AF:

0.000532

AC:

AN:

152372

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00104

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00104

Hom.:

Bravo

AF:

0.000548

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000569

AC:

EpiCase

AF:

0.00131

EpiControl

AF:

0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, ovarian, or lung cancer (Matakidou 2006, Maxwell 2016); This variant is associated with the following publications: (PMID: 24728327, 16550608, 27153395) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 02, 2018	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Uncertain:2Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 07, 2023	Variant summary: ERCC4 c.16C>T (p.Pro6Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 242132 control chromosomes. The observed variant frequency is approximately 2.37 fold of the estimated maximal expected allele frequency for a pathogenic variant in ERCC4 causing Xeroderma Pigmentosum phenotype (0.00019), suggesting that the variant may be benign. However no homozygous control individuals were observed. c.16C>T has been reported in the literature in at least one heterozygous individual affected with familial early-onset skin cancer without evidence of cosegregation (e.g. Matakidou_2006). These report(s) do not provide unequivocal conclusions about association of the variant with Xeroderma Pigmentosum. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, all classifying the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 18, 2022	DNA sequence analysis of the ERCC4 gene demonstrated a sequence change, c.16C>T, in exon 1 that results in an amino acid change, p.Pro6Ser. This sequence change has been previously described in individuals with lung cancer (PMID: 16550608) and breast and/or ovarian cancer (PMID: 27153395). This sequence change has been described in the gnomAD database with a frequency of 0.09% in the European subpopulation (dbSNP rs61760160). The p.Pro6Ser change affects a poorly conserved amino acid residue located in a domain of the ERCC4 protein that is known to be functional. The p.Pro6Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro6Ser change remains unknown at this time. -

Fanconi anemia complementation group Q

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 22, 2022	The ERCC4 c.16C>T (p.Pro6Ser) missense change has a maximum subpopulation frequency of 0.093% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with a personal and/or family history of lung cancer (PMID: 16550608) and breast cancer (PMID: 27153395). To our knowledge, this variant has not been reported in individuals with Fanconi anemia or Xeroderma pigmentosum. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 13, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Xeroderma pigmentosum, group F

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 6 of the ERCC4 protein (p.Pro6Ser). This variant is present in population databases (rs61760160, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with lung cancer (PMID: 16550608). ClinVar contains an entry for this variant (Variation ID: 134131). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Xeroderma pigmentosum

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Sep 15, 2021

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 04, 2022

The c.16C>T (p.P6S) alteration is located in exon 1 (coding exon 1) of the ERCC4 gene. This alteration results from a C to T substitution at nucleotide position 16, causing the proline (P) at amino acid position 6 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Mar 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

7.5

DANN

Benign

0.88

DEOGEN2

Benign

0.097

.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.46

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;L

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.060

.;N

REVEL

Uncertain

0.30

Sift

Benign

0.28

.;T

Sift4G

Benign

0.38

T;T

Polyphen

0.0

.;B

Vest4

0.66

MVP

0.68

MPC

0.078

ClinPred

0.039

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.5

Varity_R

0.023

gMVP

0.44

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

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