rs3136056

Positions:

chr16-13922075-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_005236.3(ERCC4):c.252C>T(p.Leu84Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00789 in 1,613,702 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0090 ( 21 hom., cov: 32)

Exomes 𝑓: 0.0078 ( 119 hom. )

Consequence

ERCC4
NM_005236.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.339

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 Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 16-13922075-C-T is Benign according to our data. Variant chr16-13922075-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 240124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-13922075-C-T is described in Lovd as [Benign]. Variant chr16-13922075-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.339 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC4	NM_005236.3 linkuse as main transcript	c.252C>T	p.Leu84Leu	synonymous_variant	2/11	ENST00000311895.8	NP_005227.1	Q92889-1A0A1W1GSK9
ERCC4	XM_011522424.4 linkuse as main transcript	c.252C>T	p.Leu84Leu	synonymous_variant	2/12		XP_011520726.1	A0A804HKF9
LOC105371093	XR_007064999.1 linkuse as main transcript	n.82+4450G>A		intron_variant
LOC105371093	XR_007065000.1 linkuse as main transcript	n.82+4450G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8 linkuse as main transcript	c.252C>T	p.Leu84Leu	synonymous_variant	2/11	1	NM_005236.3	ENSP00000310520.7		Q92889-1

Frequencies

GnomAD3 genomes

AF:

0.00903

AC:

1373

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00114

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00950

Gnomad EAS

AF:

0.000965

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0657

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00781

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.0100

AC:

2522

AN:

251282

Hom.:

AF XY:

0.00975

AC XY:

1324

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.00962

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00160

Gnomad FIN exome

AF:

0.0646

Gnomad NFE exome

AF:

0.00778

Gnomad OTH exome

AF:

0.00848

GnomAD4 exome

AF:

0.00777

AC:

11356

AN:

1461518

Hom.:

119

Cov.:

AF XY:

0.00752

AC XY:

5465

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.000837

Gnomad4 AMR exome

AF:

0.000939

Gnomad4 ASJ exome

AF:

0.0101

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00179

Gnomad4 FIN exome

AF:

0.0578

Gnomad4 NFE exome

AF:

0.00664

Gnomad4 OTH exome

AF:

0.00656

GnomAD4 genome

AF:

0.00902

AC:

1373

AN:

152184

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

820

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00262

Gnomad4 ASJ

AF:

0.00950

Gnomad4 EAS

AF:

0.000967

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0657

Gnomad4 NFE

AF:

0.00781

Gnomad4 OTH

AF:

0.00663

Alfa

AF:

0.00659

Hom.:

Bravo

AF:

0.00419

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00551

EpiControl

AF:

0.00581

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Xeroderma pigmentosum, group F

Benign:2

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	Illumina Laboratory Services, Illumina	Jan 13, 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 provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ERCC4: BP4, BP7, BS2 -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

8.2

DANN

Benign

0.80

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

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