rs4150521

chr2-127259402-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000122.2(ERCC3):c.2111C>T(p.Ser704Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00249 in 1,614,128 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S704S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (9 hom.)
• Consequence: ERCC3 NM_000122.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:8 O:1
• Conservation: PhyloP100: 5.32

Genes affected

ERCC3 (HGNC:3435): (ERCC excision repair 3, TFIIH core complex helicase subunit) This gene encodes an ATP-dependent DNA helicase that functions in nucleotide excision repair. The encoded protein is a subunit of basal transcription factor 2 (TFIIH) and, therefore, also functions in class II transcription. Mutations in this gene are associated with Xeroderma pigmentosum B, Cockayne's syndrome, and trichothiodystrophy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008400142).
• BP6: Variant 2-127259402-G-A is Benign according to our data. Variant chr2-127259402-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC3	NM_000122.2	c.2111C>T	p.Ser704Leu	missense_variant	14/15	ENST00000285398.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC3	ENST00000285398.7	c.2111C>T	p.Ser704Leu	missense_variant	14/15	1	NM_000122.2	P1

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 341 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00622

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00267

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00220 AC: 552 AN: 251336 Hom.: 2 AF XY: 0.00215 AC XY: 292 AN XY: 135836

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00702

Gnomad NFE exome AF: 0.00210

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00251 AC: 3675 AN: 1461888 Hom.: 9 Cov.: 31 AF XY: 0.00238 AC XY: 1730 AN XY: 727246

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.00914

Gnomad4 NFE exome AF: 0.00256

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00224 AC: 341 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.00245 AC XY: 182 AN XY: 74434

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00622

Gnomad4 NFE AF: 0.00268

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00236 Hom.: 1

Bravo AF: 0.00175

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00217 AC: 264

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2 Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2 Benign:4

Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ERCC3 p.Ser640Leu variant was not identified in the literature but was identified in dbSNP (ID: rs4150521) and ClinVar (classified as benign by Invitae; likely benign by Mendelics for Xeroderma pigmentosum, complementation group b and uncertain significance by CeGaT Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 607 of 268178 chromosomes (2 homozygous) at a frequency of 0.002263 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: European (Finnish) in 182 of 25100 chromosomes (freq: 0.007251), Other in 32 of 6702 chromosomes (freq: 0.004775), Latino in 103 of 35102 chromosomes (freq: 0.002934), European (non-Finnish) in 257 of 118038 chromosomes (freq: 0.002177), Ashkenazi Jewish in 12 of 9854 chromosomes (freq: 0.001218), African in 12 of 23604 chromosomes (freq: 0.000508) and South Asian in 9 of 30526 chromosomes (freq: 0.000295), but was not observed in the East Asian population. The p.Ser640 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28259476, 27153395, 31346352, 30256826, 16550608, 30414346, 16574953, 24728327) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	ERCC3: BS2 -

Xeroderma pigmentosum group B Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Xeroderma pigmentosum Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Jan 12, 2022

- -

ERCC3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 25, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.0084	T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.3	D;.
REVEL	Benign	0.23
Sift	Benign	0.043	D;.
Sift4G	Uncertain	0.053	T;.
Polyphen		0.64	P;.
Vest4		0.27
MVP		0.85
MPC		0.32
ClinPred		0.022	T
GERP RS		5.5
Varity_R		0.27
gMVP		0.60

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: rs4150521; hg19: chr2-128016978; COSMIC: COSV104535515; COSMIC: COSV104535515;