rs201494527

Variant names:

• chr2-171448666-TC-T
• rs201494527
• NM_025000.4:c.322-14delC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_025000.4(DCAF17):​c.322-14delC variant causes a 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 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.977
• 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: Likely_benign. The variant received -1 ACMG points.

• 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 VariationId is 191309.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCAF17	NM_025000.4	c.322-14delC		intron_variant	Intron 3 of 13	ENST00000375255.8	NP_079276.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCAF17	ENST00000375255.8	c.322-14delC		intron_variant	Intron 3 of 13	1	NM_025000.4	ENSP00000364404.3

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

GnomAD2 exomes AF: 0.00145 AC: 201 AN: 138356 AF XY: 0.00150

Gnomad AFR exome AF: 0.000667

Gnomad AMR exome AF: 0.00552

Gnomad ASJ exome AF: 0.00121

Gnomad EAS exome AF: 0.000917

Gnomad FIN exome AF: 0.000789

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00222

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000300 AC: 9 AN: 30036

American (AMR) AF: 0.00187 AC: 58 AN: 31058

Ashkenazi Jewish (ASJ) AF: 0.000340 AC: 8 AN: 23510

East Asian (EAS) AF: 0.000398 AC: 15 AN: 37664

South Asian (SAS) AF: 0.00101 AC: 73 AN: 72484

European-Finnish (FIN) AF: 0.000413 AC: 21 AN: 50856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5154

European-Non Finnish (NFE) AF: 0.000252 AC: 269 AN: 1068462

Other (OTH) AF: 0.000497 AC: 28 AN: 56286

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000346 AC: 1 AN: 28900

American (AMR) AF: 0.000116 AC: 1 AN: 8588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1930

East Asian (EAS) AF: 0.00 AC: 0 AN: 3462

South Asian (SAS) AF: 0.00 AC: 0 AN: 2518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 178

European-Non Finnish (NFE) AF: 0.0000457 AC: 2 AN: 43722

Other (OTH) AF: 0.00 AC: 0 AN: 1314

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0339446), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

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

Jun 08, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Downgraded variant due to updated local frequency -

Jun 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DCAF17-related disorder Benign:1

Nov 02, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.98
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs201494527; hg19: chr2-172305176;