rs397509400

Positions:

• chr16-13935413-TAACTC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 5.72

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]

(HGNC:):

ACMG classification

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	UniProt
ERCC4	NM_005236.3	c.1484_1488del	p.Thr495AsnfsTer6	frameshift_variant	8/11	ENST00000311895.8	NP_005227.1
ERCC4	XM_011522424.4	c.1622_1626del	p.Thr541AsnfsTer6	frameshift_variant	9/12		XP_011520726.1
ERCC4	XM_011522427.2	c.134_138del	p.Thr45AsnfsTer6	frameshift_variant	3/6		XP_011520729.1
ERCC4	XM_047433774.1	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	c.1484_1488del	p.Thr495AsnfsTer6	frameshift_variant	8/11	1	NM_005236.3	ENSP00000310520	P1
	ENST00000570663.1	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.: 32

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 249934 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135208

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: 25 AN: 1460740 Hom.: 0 AF XY: 0.0000165 AC XY: 12 AN XY: 726618

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397509400; hg19: chr16-14029270;