2-171448667-C-T

Variant names:

• chr2-171448667-C-T
• rs192861143
• NM_025000.4:c.322-14C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_025000.4(DCAF17):​c.322-14C>T variant causes a 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 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• 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: Benign. The variant received -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 VariationId is 191260.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025000.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCAF17	NM_025000.4	MANE Select	c.322-14C>T		intron	N/A	NP_079276.2
	DCAF17	NM_001164821.2		c.322-14C>T		intron	N/A	NP_001158293.1
	DCAF17	NR_028482.2		n.674-14C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCAF17	ENST00000375255.8	TSL:1 MANE Select	c.322-14C>T		intron	N/A	ENSP00000364404.3
	DCAF17	ENST00000966668.1		c.373-14C>T		intron	N/A	ENSP00000636727.1
	DCAF17	ENST00000907633.1		c.313-14C>T		intron	N/A	ENSP00000577692.1

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

GnomAD2 exomes AF: 0.316 AC: 41589 AN: 131666 AF XY: 0.321

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 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

African (AFR) AF: 0.186 AC: 4697 AN: 25310

American (AMR) AF: 0.347 AC: 9580 AN: 27630

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 5620 AN: 20696

East Asian (EAS) AF: 0.262 AC: 8779 AN: 33488

South Asian (SAS) AF: 0.300 AC: 19327 AN: 64440

European-Finnish (FIN) AF: 0.222 AC: 9741 AN: 43826

Middle Eastern (MID) AF: 0.221 AC: 1010 AN: 4574

European-Non Finnish (NFE) AF: 0.220 AC: 200399 AN: 909422

Other (OTH) AF: 0.234 AC: 11348 AN: 48412

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

African (AFR) AF: 0.170 AC: 6767 AN: 39912

American (AMR) AF: 0.273 AC: 4040 AN: 14780

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 888 AN: 3424

East Asian (EAS) AF: 0.199 AC: 999 AN: 5028

South Asian (SAS) AF: 0.289 AC: 1343 AN: 4654

European-Finnish (FIN) AF: 0.224 AC: 2000 AN: 8914

Middle Eastern (MID) AF: 0.240 AC: 69 AN: 288

European-Non Finnish (NFE) AF: 0.201 AC: 13295 AN: 66198

Other (OTH) AF: 0.225 AC: 455 AN: 2024

Alfa AF: 0.169 Hom.: 708

Bravo AF: 0.201

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	Woodhouse-Sakati syndrome (7)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.31
DANN	Benign	0.19
PhyloP100		-0.98
Mutation Taster		=47/53	disease causing

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

Other links and lift over

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