rs201494527

Positions:

• chr2-171448666-TC-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP6 BS1

The NM_025000.4(DCAF17):​c.322-14del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00035 in 1,375,510 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000041 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DCAF17 NM_025000.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.977

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 2-171448666-TC-T is Benign according to our data. Variant chr2-171448666-TC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191309.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00035 (481/1375510) while in subpopulation AMR AF= 0.00187 (58/31058). AF 95% confidence interval is 0.00148. There are 0 homozygotes in gnomad4_exome. There are 261 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCAF17	NM_025000.4	c.322-14del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000375255.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCAF17	ENST00000375255.8	c.322-14del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_025000.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000410 AC: 4 AN: 97604 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000347

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000117

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000457

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000350 AC: 481 AN: 1375510 Hom.: 0 Cov.: 31 AF XY: 0.000384 AC XY: 261 AN XY: 680140

Gnomad4 AFR exome AF: 0.000300

Gnomad4 AMR exome AF: 0.00187

Gnomad4 ASJ exome AF: 0.000340

Gnomad4 EAS exome AF: 0.000398

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.000413

Gnomad4 NFE exome AF: 0.000252

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000409 AC: 4 AN: 97686 Hom.: 0 Cov.: 31 AF XY: 0.0000420 AC XY: 2 AN XY: 47626

Gnomad4 AFR AF: 0.0000346

Gnomad4 AMR AF: 0.000116

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000457

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Woodhouse-Sakati syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Uncertain significance, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Jun 08, 2024	Downgraded variant due to updated local frequency -

DCAF17-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 02, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201494527; hg19: chr2-172305176;