rs146556466

Positions:

• chr2-171435068-C-A
• chr2-171435068-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025000.4(DCAF17):​c.127-15C>A 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 0.000887 in 1,564,188 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (9 hom.)
• Consequence: DCAF17 NM_025000.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.466

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-171435068-C-A is Benign according to our data. Variant chr2-171435068-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 332260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00206 (313/152254) while in subpopulation AMR AF= 0.0152 (233/15290). AF 95% confidence interval is 0.0136. There are 7 homozygotes in gnomad4. There are 173 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCAF17	NM_025000.4	c.127-15C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000375255.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCAF17	ENST00000375255.8	c.127-15C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_025000.4	P1

Frequencies

GnomAD3 genomes AF: 0.00203 AC: 309 AN: 152136 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00865

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00255 AC: 634 AN: 248924 Hom.: 5 AF XY: 0.00207 AC XY: 280 AN XY: 135080

Gnomad AFR exome AF: 0.000583

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00809

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.000761 AC: 1075 AN: 1411934 Hom.: 9 Cov.: 26 AF XY: 0.000736 AC XY: 519 AN XY: 705538

Gnomad4 AFR exome AF: 0.000311

Gnomad4 AMR exome AF: 0.0143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00943

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000937

Gnomad4 OTH exome AF: 0.000716

GnomAD4 genome AF: 0.00206 AC: 313 AN: 152254 Hom.: 7 Cov.: 33 AF XY: 0.00232 AC XY: 173 AN XY: 74454

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.0152

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00867

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.00261

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Woodhouse-Sakati syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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 rs146556466, yet. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 20, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.7
DANN	Benign	0.54

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: rs146556466; hg19: chr2-172291578;