rs192861143

chr2-171448667-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_025000.4(DCAF17):c.322-14C>T 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 0.227 in 1,323,918 control chromosomes in the GnomAD database, including 30,787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.21 (3118 hom., cov: 31)
  • Exomes 𝑓: 0.23 (27669 hom.)
• Consequence: DCAF17 NM_025000.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:10
• 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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-171448667-C-T is Benign according to our data. Variant chr2-171448667-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191260.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5}. Variant chr2-171448667-C-T is described in Lovd as [Benign]. Variant chr2-171448667-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.205 AC: 29987 AN: 146066 Hom.: 3113 Cov.: 31

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.221

GnomAD3 exomes AF: 0.316 AC: 41589 AN: 131666 Hom.: 4823 AF XY: 0.321 AC XY: 22999 AN XY: 71588

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.435

Gnomad ASJ exome AF: 0.357

Gnomad EAS exome AF: 0.259

Gnomad SAS exome AF: 0.386

Gnomad FIN exome AF: 0.312

Gnomad NFE exome AF: 0.288

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.230 AC: 270501 AN: 1177798 Hom.: 27669 Cov.: 31 AF XY: 0.231 AC XY: 134832 AN XY: 583216

Gnomad4 AFR exome AF: 0.186

Gnomad4 AMR exome AF: 0.347

Gnomad4 ASJ exome AF: 0.272

Gnomad4 EAS exome AF: 0.262

Gnomad4 SAS exome AF: 0.300

Gnomad4 FIN exome AF: 0.222

Gnomad4 NFE exome AF: 0.220

Gnomad4 OTH exome AF: 0.234

GnomAD4 genome AF: 0.205 AC: 30011 AN: 146120 Hom.: 3118 Cov.: 31 AF XY: 0.207 AC XY: 14717 AN XY: 70936

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.273

Gnomad4 ASJ AF: 0.259

Gnomad4 EAS AF: 0.199

Gnomad4 SAS AF: 0.289

Gnomad4 FIN AF: 0.224

Gnomad4 NFE AF: 0.201

Gnomad4 OTH AF: 0.225

Alfa AF: 0.0996 Hom.: 142

Bravo AF: 0.201

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Woodhouse-Sakati syndrome Benign:6

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Mutations in DCAF17 have been associated with a rare syndrome called Woodhouse Sakati Syndrome, which can have diabetes mellitus as one of the presentations.However no sufficient evidence is found to ascertain the role of this particular variant rs192861143, yet. -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Oct 04, 2021	Population allele frequency is 30% (rs192861143, 46,946/157,936 alleles, 5344 homozygotes in gnomAD v2.1). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria met: BA1 -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Pathogenic:1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, criteria provided, single submitter	research	Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.31
Dann	Benign	0.19

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: rs192861143; hg19: chr2-172305177; COSMIC: COSV59829689; COSMIC: COSV59829689;