Variant 2-171434578-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_025000.4(DCAF17):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,374,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

DCAF17
NM_025000.4 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.361

Variant links:

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 links:

METTL8 (HGNC:25856): (methyltransferase 8, tRNA N3-cytidine) Enables mRNA methyltransferase activity. Involved in mRNA methylation. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

METTL8 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-171434578-A-G is Pathogenic according to our data. Variant chr2-171434578-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2960660.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-171434578-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCAF17	NM_025000.4 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/14	ENST00000375255.8	NP_079276.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCAF17	ENST00000375255.8 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/14	1	NM_025000.4	ENSP00000364404	P1	Q5H9S7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000241

AC:

AN:

124632

Hom.:

AF XY:

0.0000293

AC XY:

AN XY:

68326

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000137

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1374922

Hom.:

Cov.:

AF XY:

0.0000162

AC XY:

AN XY:

678312

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000191

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000131

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Woodhouse-Sakati syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change affects the initiator methionine of the DCAF17 mRNA. The next in-frame methionine is located at codon 88. This variant is present in population databases (rs762608997, gnomAD 0.01%). Disruption of the initiator codon has been observed in individual(s) with Woodhouse-Sakati syndrome (PMID: 31323129). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0065

.;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.099

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;D

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.11

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.90

P;B

Vest4

0.56

MutPred

1.0

Loss of glycosylation at P3 (P = 0.0796);Loss of glycosylation at P3 (P = 0.0796);

MVP

0.34

ClinPred

0.93

GERP RS

-0.13

Varity_R

0.85

gMVP

0.51

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over