Variant chr16-13935413-TAACTC-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_005236.3(ERCC4):c.1484_1488del(p.Thr495AsnfsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000171 in 1,460,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ERCC4
NM_005236.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 5.72

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:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-13935413-TAACTC-T is Pathogenic according to our data. Variant chr16-13935413-TAACTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 55823.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-13935413-TAACTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ERCC4	NM_005236.3 linkuse as main transcript	c.1484_1488del	p.Thr495AsnfsTer6	frameshift_variant	8/11	ENST00000311895.8	NP_005227.1
ERCC4	XM_011522424.4 linkuse as main transcript	c.1622_1626del	p.Thr541AsnfsTer6	frameshift_variant	9/12		XP_011520726.1
ERCC4	XM_011522427.2 linkuse as main transcript	c.134_138del	p.Thr45AsnfsTer6	frameshift_variant	3/6		XP_011520729.1
ERCC4	XM_047433774.1 linkuse as main transcript	c.695_699del	p.Thr232AsnfsTer6	frameshift_variant	5/8		XP_047289730.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8 linkuse as main transcript	c.1484_1488del	p.Thr495AsnfsTer6	frameshift_variant	8/11	1	NM_005236.3	ENSP00000310520	P1	Q92889-1
	ENST00000570663.1 linkuse as main transcript	n.218_219+3del		splice_donor_variant, splice_donor_region_variant, non_coding_transcript_exon_variant, intron_variant	1/2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

249934

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135208

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1460740

Hom.:

AF XY:

0.0000165

AC XY:

AN XY:

726618

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Fanconi anemia complementation group Q

Pathogenic:2

Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Oct 03, 2014	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 02, 2013	- -

Precursor B-cell acute lymphoblastic leukemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Jul 26, 2018

This is a frameshift alteration in which coding nucleotides 1484 through 1488 are deleted. This is predicted to change a Threonine to an Asparagine at codon 495, as well as shift the reading frame and result in a premature stop codon 6 amino acids downstream. Classification criteria: PVS1, PS3, PM2, PP1. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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