rs797045038

Positions:

• chr2-171448794-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 18P and 1B. PVS1 PM2 PP5_Very_Strong BS1_Supporting

The NM_025000.4(DCAF17):​c.436delC​(p.Ala147fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000958 in 1,460,826 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: 0.0000096 (0 hom.)
• Consequence: DCAF17 NM_025000.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 6.09

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]

DCAF17 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 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 2-171448794-TC-T is Pathogenic according to our data. Variant chr2-171448794-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 209146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-171448794-TC-T is described in Lovd as [Pathogenic]. Variant chr2-171448794-TC-T is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000958 (14/1460826) while in subpopulation MID AF= 0.00226 (13/5764). AF 95% confidence interval is 0.00133. There are 0 homozygotes in gnomad4_exome. There are 7 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCAF17	NM_025000.4	c.436delC	p.Ala147fs	frameshift_variant	4/14	ENST00000375255.8	NP_079276.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCAF17	ENST00000375255.8	c.436delC	p.Ala147fs	frameshift_variant	4/14	1	NM_025000.4	ENSP00000364404.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1460826 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 726786

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Woodhouse-Sakati syndrome Pathogenic:7 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 15, 2021	This sequence change creates a premature translational stop signal (p.Ala147Hisfs*9) 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). This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individuals with Woodhouse-Sakati syndrome (PMID: 19026396, 24015686, 26664771). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 209146). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 05, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 21, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 24, 2014	This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 23-year-old male with diabetes, dystonia, coordination difficulties, thumb stiffening, ulnar deviation of the hand, hypernasal voice, hypothyroidism, hypogonadism, chronic facial and extremity edema and erythema, similarly affected sib (not tested). Variant pathogenic in recessive state; heterozygotes are carriers. -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Aug 25, 2019	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	May 08, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2008	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	DCAF17: PVS1, PM2, PM3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2021	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26633545, 6876115, 26664771, 24015686, 29574468, 32033986, 32552793, 33543475, 31589614, 33144682, 33098801, 19026396) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	-	- -

DCAF17-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 09, 2024

The DCAF17 c.436delC variant is predicted to result in a frameshift and premature protein termination (p.Ala147Hisfs*9). This variant has been reported in multiple families with autosomal recessive Woodhouse-Sakati syndrome (see for examples Alazami et al. 2008. PubMed ID: 19026396, Maddirevula et al. 2020. PubMed ID: 32552793, Nanda et al. 2014. PubMed ID: 24015686). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in DCAF17 are expected to be pathogenic. This variant is interpreted as pathogenic. -

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: rs797045038; hg19: chr2-172305304;