rs869025184

Positions:

• chr16-13947895-TTCTC-T
• chr16-13947895-TTCTC-TTC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_005236.3(ERCC4):​c.2304_2307del​(p.Thr770ProfsTer46) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERCC4 NM_005236.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.45

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-13947895-TTCTC-T is Pathogenic according to our data. Variant chr16-13947895-TTCTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 16579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-13947895-TTCTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC4	NM_005236.3	c.2304_2307del	p.Thr770ProfsTer46	frameshift_variant	11/11	ENST00000311895.8	NP_005227.1
ERCC4	XM_011522424.4	c.2442_2445del	p.Thr816ProfsTer46	frameshift_variant	12/12		XP_011520726.1
ERCC4	XM_011522427.2	c.954_957del	p.Thr320ProfsTer46	frameshift_variant	6/6		XP_011520729.1
ERCC4	XM_047433774.1	c.1515_1518del	p.Thr507ProfsTer46	frameshift_variant	8/8		XP_047289730.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8	c.2304_2307del	p.Thr770ProfsTer46	frameshift_variant	11/11	1	NM_005236.3	ENSP00000310520	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Xeroderma pigmentosum, group F Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 06, 1996

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs869025184; hg19: chr16-14041752;