chr2-171448666-TC-T

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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Genomics England PanelApp, Orphanet

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCAF17	NM_025000.4	MANE Select	c.322-14delC		intron	N/A	NP_079276.2	Q5H9S7-1
	DCAF17	NM_001164821.2		c.322-14delC		intron	N/A	NP_001158293.1	F5H7W1
	DCAF17	NR_028482.2		n.674-14delC		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCAF17	ENST00000375255.8	TSL:1 MANE Select	c.322-14delC		intron	N/A	ENSP00000364404.3	Q5H9S7-1
	DCAF17	ENST00000966668.1		c.373-14delC		intron	N/A	ENSP00000636727.1
	DCAF17	ENST00000907633.1		c.313-14delC		intron	N/A	ENSP00000577692.1

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Woodhouse-Sakati syndrome (2)
-	-	1	DCAF17-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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;