rs1800068

chr16-13935659-G-Cchr16-13935659-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005236.3(ERCC4):c.1727G>C(p.Arg576Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00128 in 1,614,124 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R576S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00083 (0 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:11 B:1 O:1
• Conservation: PhyloP100: 6.07

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14403656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC4	NM_005236.3	c.1727G>C	p.Arg576Thr	missense_variant	8/11	ENST00000311895.8
ERCC4	XM_011522424.4	c.1865G>C	p.Arg622Thr	missense_variant	9/12
ERCC4	XM_047433774.1	c.938G>C	p.Arg313Thr	missense_variant	5/8
ERCC4	XM_011522427.2	c.377G>C	p.Arg126Thr	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC4	ENST00000311895.8	c.1727G>C	p.Arg576Thr	missense_variant	8/11	1	NM_005236.3	P1
	ENST00000570663.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.000828 AC: 126 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

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: 0.00113

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000688 AC: 172 AN: 250108 Hom.: 0 AF XY: 0.000635 AC XY: 86 AN XY: 135332

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00133 AC: 1942 AN: 1461836 Hom.: 1 Cov.: 32 AF XY: 0.00131 AC XY: 950 AN XY: 727216

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00161

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.000827 AC: 126 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000819 AC XY: 61 AN XY: 74464

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000871 Hom.: 0

Bravo AF: 0.00101

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000544 AC: 66

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ERCC4 p.Arg576Thr variant was identified in 10 of 6374 proband chromosomes (frequency: 0.001569) from individuals with breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma or head and neck squamous cell carcinoma and was present in 2 of 154 control chromosomes (frequency: 0.01299) from healthy individuals (McVeigh_2020_PMID:32008151; West_2018; Shindo_2017_PMID:28767289; Chandrasekharappa_2017_PMID:28678401). The variant was identified in dbSNP (ID: rs1800068) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 185 of 281516 chromosomes at a frequency of 0.0006572 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 45 of 35426 chromosomes (freq: 0.00127), European (non-Finnish) in 126 of 127888 chromosomes (freq: 0.000985), Other in 7 of 7216 chromosomes (freq: 0.00097), African in 5 of 24972 chromosomes (freq: 0.0002) and European (Finnish) in 2 of 25102 chromosomes (freq: 0.00008), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Arg576 residue is conserved in mammals 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional assays demonstrated defective DNA repair function after UV-induced DNA damage with ERCC4 p.R576T compared to wildtype (West_2018). 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. -

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	Aug 17, 2022	The ERCC4 c.1727G>C (p.Arg576Thr) missense change has a maximum subpopulation frequency of 0.13% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with breast cancer (PMID: 32008151, 34117267), head and neck squamous cell carcinoma (PMID: 28678401), and pancreatic ductal adenocarcinoma (PMID: 28767289). 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	Sep 26, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 09, 2021	DNA sequence analysis of the ERCC4 gene demonstrated a sequence change, c.1727G>C, in exon 8 that results in an amino acid change, p.Arg576Thr. This sequence change has been described in the gnomAD database with a frequency of 0.13% in the Latino sub-population (dbSNP rs1800068). The p.Arg576Thr change has been reported in individuals with head and neck carcinoma and pancreatic cancer (PMIDs: 28678401, 28767289). The p.Arg576Thr change affects a moderately conserved amino acid residue located in a domain of the ERCC4 protein that is known to be functional. The p.Arg576Thr substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg576Thr change remains unknown at this time. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Xeroderma pigmentosum Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Jan 04, 2022

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 16, 2021

The c.1727G>C (p.R576T) alteration is located in exon 8 (coding exon 8) of the ERCC4 gene. This alteration results from a G to C substitution at nucleotide position 1727, causing the arginine (R) at amino acid position 576 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Xeroderma pigmentosum, group F Uncertain:1

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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Jul 16, 2021

ERCC4 NM_005236.2 exon 8 p.Arg576Thr (c.1727G>C):This variant has been reported in the literature in at least 4 individuals: 1 with head/neck squamous cell carcinoma, 3 with pancreatic ductal adenocarcinoma (Chanrasekharappa 2017 PMID:28678401, Shindo 2017 PMID:28767289). This variant is present in 0.1% (29/15276) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-13935659-G-C?dataset=gnomad_r3) This variant is present in ClinVar (Variation ID:134158). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	23
Dann	Benign	0.97
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.27
Sift	Benign	0.094	T
Sift4G	Benign	0.076	T
Polyphen		0.88	P
Vest4		0.78
MVP		0.79
MPC		0.14
ClinPred		0.090	T
GERP RS		5.3
Varity_R		0.28
gMVP		0.76

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: rs1800068; hg19: chr16-14029516; COSMIC: COSV104606285; COSMIC: COSV104606285;