rs2020955

chr16-13944802-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005236.3(ERCC4):c.1984T>C(p.Ser662Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,613,574 control chromosomes in the GnomAD database, including 1,719 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (904 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (815 hom.)
• Consequence: ERCC4 NM_005236.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.463

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011295676).
• BP6: Variant 16-13944802-T-C is Benign according to our data. Variant chr16-13944802-T-C is described in ClinVar as [Benign]. Clinvar id is 134134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC4	NM_005236.3	c.1984T>C	p.Ser662Pro	missense_variant	10/11	ENST00000311895.8
ERCC4	XM_011522424.4	c.2122T>C	p.Ser708Pro	missense_variant	11/12
ERCC4	XM_047433774.1	c.1195T>C	p.Ser399Pro	missense_variant	7/8
ERCC4	XM_011522427.2	c.634T>C	p.Ser212Pro	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC4	ENST00000311895.8	c.1984T>C	p.Ser662Pro	missense_variant	10/11	1	NM_005236.3	P1

Frequencies

GnomAD3 genomes AF: 0.0588 AC: 8952 AN: 152194 Hom.: 903 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0239

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0473

GnomAD3 exomes AF: 0.0157 AC: 3954 AN: 251158 Hom.: 329 AF XY: 0.0120 AC XY: 1631 AN XY: 135712

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00784

GnomAD4 exome AF: 0.00669 AC: 9778 AN: 1461262 Hom.: 815 Cov.: 30 AF XY: 0.00588 AC XY: 4273 AN XY: 726982

Gnomad4 AFR exome AF: 0.214

Gnomad4 AMR exome AF: 0.0131

Gnomad4 ASJ exome AF: 0.0106

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000452

Gnomad4 FIN exome AF: 0.000487

Gnomad4 NFE exome AF: 0.000701

Gnomad4 OTH exome AF: 0.0137

GnomAD4 genome AF: 0.0589 AC: 8967 AN: 152312 Hom.: 904 Cov.: 32 AF XY: 0.0561 AC XY: 4178 AN XY: 74482

Gnomad4 AFR AF: 0.202

Gnomad4 AMR AF: 0.0238

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.0468

Alfa AF: 0.0130 Hom.: 265

Bravo AF: 0.0669

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.192 AC: 845

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.0190 AC: 2304

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00142

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group F Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	4.5
Dann	Benign	0.66
DEOGEN2	Benign	0.085	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.27	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.015
Sift	Benign	0.43	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.099
MPC		0.098
ClinPred		0.000022	T
GERP RS		0.88
Varity_R		0.074
gMVP		0.16

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: rs2020955; hg19: chr16-14038659; COSMIC: COSV61312310;