chr2-171448794-TC-T

Variant names:

• chr2-171448794-TC-T
• rs797045038
• NM_025000.4:c.436delC

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1 PP5_Very_Strong BS1_Supporting

The NM_025000.4(DCAF17):​c.436delC​(p.Ala147HisfsTer9) 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:14 O:1
• Conservation: PhyloP100: 6.09
• Publications: 22 publications found

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 Gene-Disease associations (from GenCC):

• Woodhouse-Sakati syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, ClinGen, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-171448794-TC-T is Pathogenic according to our data. Variant chr2-171448794-TC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 209146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 7 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025000.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCAF17	NM_025000.4	MANE Select	c.436delC	p.Ala147HisfsTer9	frameshift	Exon 4 of 14	NP_079276.2
	DCAF17	NM_001164821.2		c.436delC	p.Ala147HisfsTer9	frameshift	Exon 4 of 12	NP_001158293.1
	DCAF17	NR_028482.2		n.788delC		non_coding_transcript_exon	Exon 4 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCAF17	ENST00000375255.8	TSL:1 MANE Select	c.436delC	p.Ala147HisfsTer9	frameshift	Exon 4 of 14	ENSP00000364404.3
	DCAF17	ENST00000966668.1		c.487delC	p.Ala164HisfsTer9	frameshift	Exon 5 of 15	ENSP00000636727.1
	DCAF17	ENST00000907633.1		c.427delC	p.Ala144HisfsTer9	frameshift	Exon 4 of 14	ENSP00000577692.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 86114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111296

Other (OTH) AF: 0.0000166 AC: 1 AN: 60358

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Woodhouse-Sakati syndrome (9)
5	-	-	not provided (5)
1	-	-	DCAF17-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797045038; hg19: chr2-172305304;