2-171448700-C-T

Variant names:

• chr2-171448700-C-T
• rs760978794
• NM_025000.4:c.341C>T
• DCAF17 p.Ser114Leu

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025000.4(DCAF17):​c.341C>T​(p.Ser114Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DCAF17 NM_025000.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.24
• 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: Genomics England PanelApp, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11352855).

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.341C>T	p.Ser114Leu	missense	Exon 4 of 14	NP_079276.2	Q5H9S7-1
	DCAF17	NM_001164821.2		c.341C>T	p.Ser114Leu	missense	Exon 4 of 12	NP_001158293.1	F5H7W1
	DCAF17	NR_028482.2		n.693C>T		non_coding_transcript_exon	Exon 4 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCAF17	ENST00000375255.8	TSL:1 MANE Select	c.341C>T	p.Ser114Leu	missense	Exon 4 of 14	ENSP00000364404.3	Q5H9S7-1
	DCAF17	ENST00000966668.1		c.392C>T	p.Ser131Leu	missense	Exon 5 of 15	ENSP00000636727.1
	DCAF17	ENST00000907633.1		c.332C>T	p.Ser111Leu	missense	Exon 4 of 14	ENSP00000577692.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000418 AC: 1 AN: 239250 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000309

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441252 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 715374

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

African (AFR) AF: 0.00 AC: 0 AN: 32778

American (AMR) AF: 0.0000237 AC: 1 AN: 42252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25550

East Asian (EAS) AF: 0.00 AC: 0 AN: 39262

South Asian (SAS) AF: 0.00 AC: 0 AN: 80930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102302

Other (OTH) AF: 0.00 AC: 0 AN: 59534

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.071
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0050	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.30
Mutation Taster		=95/5	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs760978794;

hg19: chr2-172305210;

COSMIC: COSV104635741;

COSMIC: COSV104635741;