rs786205638

Variant names:

• chr2-171449871-TTTAAAAGATACTTGAGCTGGGACACTCCTCAAGAAGTCATTGCAGTTA-T
• rs786205638
• NM_025000.4:c.459-7_499delTTAAAAGATACTTGAGCTGGGACACTCCTCAAGAAGTCATTGCAGTTA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_025000.4(DCAF17):​c.459-7_499delTTAAAAGATACTTGAGCTGGGACACTCCTCAAGAAGTCATTGCAGTTA​(p.Tyr154fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R153R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DCAF17 NM_025000.4 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.23
• Publications: 2 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 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-171449871-TTTAAAAGATACTTGAGCTGGGACACTCCTCAAGAAGTCATTGCAGTTA-T is Pathogenic according to our data. Variant chr2-171449871-TTTAAAAGATACTTGAGCTGGGACACTCCTCAAGAAGTCATTGCAGTTA-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 191310.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCAF17	NM_025000.4	c.459-7_499delTTAAAAGATACTTGAGCTGGGACACTCCTCAAGAAGTCATTGCAGTTA	p.Tyr154fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 5 of 14	ENST00000375255.8	NP_079276.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCAF17	ENST00000375255.8	c.459-7_499delTTAAAAGATACTTGAGCTGGGACACTCCTCAAGAAGTCATTGCAGTTA	p.Tyr154fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 5 of 14	1	NM_025000.4	ENSP00000364404.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786205638; hg19: chr2-172306381;