rs4986933

Positions:

• chr16-13948175-C-A
• chr16-13948175-C-G
• chr16-13948175-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_005236.3(ERCC4):​c.2579C>A​(p.Ala860Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000475 in 1,614,134 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).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: ERCC4 NM_005236.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7 O:1
• Conservation: PhyloP100: 2.74

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010523558).
• BP6: Variant 16-13948175-C-A is Benign according to our data. Variant chr16-13948175-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134138.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=7, Uncertain_significance=1}. Variant chr16-13948175-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC4	NM_005236.3	c.2579C>A	p.Ala860Asp	missense_variant	11/11	ENST00000311895.8
ERCC4	XM_011522424.4	c.2717C>A	p.Ala906Asp	missense_variant	12/12
ERCC4	XM_047433774.1	c.1790C>A	p.Ala597Asp	missense_variant	8/8
ERCC4	XM_011522427.2	c.1229C>A	p.Ala410Asp	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC4	ENST00000311895.8	c.2579C>A	p.Ala860Asp	missense_variant	11/11	1	NM_005236.3	P1
ERCC4	ENST00000682617.1	c.2717C>A	p.Ala906Asp	missense_variant	12/12
ERCC4	ENST00000389138.7	n.1856C>A		non_coding_transcript_exon_variant	6/6	2
ERCC4	ENST00000683962.1	c.*2273C>A		3_prime_UTR_variant, NMD_transcript_variant	12/12

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 346 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00782

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000692 AC: 174 AN: 251432 Hom.: 0 AF XY: 0.000603 AC XY: 82 AN XY: 135880

Gnomad AFR exome AF: 0.00806

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000284 AC: 415 AN: 1461888 Hom.: 1 Cov.: 33 AF XY: 0.000265 AC XY: 193 AN XY: 727248

Gnomad4 AFR exome AF: 0.00917

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.00231 AC: 352 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.00251 AC XY: 187 AN XY: 74428

Gnomad4 AFR AF: 0.00795

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000478 Hom.: 0

Bravo AF: 0.00282

ESP6500AA AF: 0.00865 AC: 38

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000807 AC: 98

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Xeroderma pigmentosum, group F Benign:3

Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 17, 2020	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Xeroderma pigmentosum Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Nov 30, 2021

- -

Hutchinson-Gilford syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

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

Jan 04, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.22
Sift	Uncertain	0.023	D
Sift4G	Benign	0.10	T
Polyphen		0.96	P
Vest4		0.62
MVP		0.61
MPC		0.36
ClinPred		0.025	T
GERP RS		6.2
Varity_R		0.35
gMVP		0.54

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: rs4986933; hg19: chr16-14042032;