rs397509401

Positions:

• chr16-13947966-T-TCTTACACTTCACTTCCCCAGACTACGGA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_005236.3(ERCC4):​c.2371_2398dup​(p.Ile800ThrfsTer24) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERCC4 NM_005236.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.35

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 8 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 16-13947966-T-TCTTACACTTCACTTCCCCAGACTACGGA is Pathogenic according to our data. Variant chr16-13947966-T-TCTTACACTTCACTTCCCCAGACTACGGA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55825.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC4	NM_005236.3	c.2371_2398dup	p.Ile800ThrfsTer24	frameshift_variant	11/11	ENST00000311895.8
ERCC4	XM_011522424.4	c.2509_2536dup	p.Ile846ThrfsTer24	frameshift_variant	12/12
ERCC4	XM_011522427.2	c.1021_1048dup	p.Ile350ThrfsTer24	frameshift_variant	6/6
ERCC4	XM_047433774.1	c.1582_1609dup	p.Ile537ThrfsTer24	frameshift_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC4	ENST00000311895.8	c.2371_2398dup	p.Ile800ThrfsTer24	frameshift_variant	11/11	1	NM_005236.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

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

Xeroderma pigmentosum, group F Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Feb 21, 2021

- -

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: rs397509401; hg19: chr16-14041823;