2-171443575-GA-GAA

Position:

• chr2-171443575-GA-GAA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_025000.4(DCAF17):​c.289dup​(p.Ile97AsnfsTer22) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DCAF17 NM_025000.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.90

Genes affected

DCAF17 (HGNC:25784): (DDB1 and CUL4 associated factor 17) This gene encodes a nuclear transmembrane protein that associates with cullin 4A/damaged DNA binding protein 1 ubiquitin ligase complex. Mutations in this gene are associated with Woodhouse-Sakati syndrome. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 2-171443575-G-GA is Pathogenic according to our data. Variant chr2-171443575-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 216916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCAF17	NM_025000.4	c.289dup	p.Ile97AsnfsTer22	frameshift_variant	3/14	ENST00000375255.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCAF17	ENST00000375255.8	c.289dup	p.Ile97AsnfsTer22	frameshift_variant	3/14	1	NM_025000.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Woodhouse-Sakati syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Apr 15, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 216916). This premature translational stop signal has been observed in individual(s) with autosomal recessive Woodhouse-Sakati syndrome (PMID: 25326637). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile97Asnfs*22) in the DCAF17 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DCAF17 are known to be pathogenic (PMID: 19026396, 20507343). -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs863224865; hg19: chr2-172300085;