2-171443558-CA-CAA

Position:

• chr2-171443558-CA-CAA

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_025000.4(DCAF17):​c.270dup​(p.Cys91MetfsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DCAF17 NM_025000.4 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.07

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 11 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 2-171443558-C-CA is Pathogenic according to our data. Variant chr2-171443558-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 632550.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCAF17	NM_025000.4	c.270dup	p.Cys91MetfsTer28	frameshift_variant	3/14	ENST00000375255.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCAF17	ENST00000375255.8	c.270dup	p.Cys91MetfsTer28	frameshift_variant	3/14	1	NM_025000.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Woodhouse-Sakati syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Hacettepe Genetic Diseases Diagnosis Center, Hacettepe University Faculty of Medicine

Dec 06, 2017

Sequencing analysis revealed a novel frameshift mutation NM_025000.4: c.270dup (p.Cys91Metfs*28) in exon 3 of DCAF17 in patient with hyper-hypogonadotropic hypogonadism, non-autoimmune insulinopenic diabetes mellitus and pituitary MRI indicated paramagnetic substance deposition in gland. These clinical findings and molecular results consistent with Woodhouse-Sakati Syndrome. Parents were found to be heterozygous carriers of this mutation. This variant was not reported in ExAC and gnomAD databases and was evaluated as pathogenic by in silico analysis such as MutationTaster. -

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: rs879253799; hg19: chr2-172300068;