2-171434467-G-T

Position:

• chr2-171434467-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_025000.4(DCAF17):​c.-111G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000776 in 1,509,542 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (4 hom.)
• Consequence: DCAF17 NM_025000.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.54

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]

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0011 (167/152222) while in subpopulation EAS AF= 0.00968 (50/5164). AF 95% confidence interval is 0.00755. There are 4 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCAF17	NM_025000.4	c.-111G>T		5_prime_UTR_variant	1/14	ENST00000375255.8	NP_079276.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCAF17	ENST00000375255.8	c.-111G>T		5_prime_UTR_variant	1/14	1	NM_025000.4	ENSP00000364404	P1

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 152104 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00966

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00726

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000942 AC: 121 AN: 128430 Hom.: 0 AF XY: 0.000939 AC XY: 66 AN XY: 70286

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00556

Gnomad SAS exome AF: 0.000582

Gnomad FIN exome AF: 0.00708

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.000740 AC: 1004 AN: 1357320 Hom.: 4 Cov.: 28 AF XY: 0.000695 AC XY: 466 AN XY: 670476

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0112

Gnomad4 SAS exome AF: 0.000590

Gnomad4 FIN exome AF: 0.00753

Gnomad4 NFE exome AF: 0.000234

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00110 AC: 167 AN: 152222 Hom.: 4 Cov.: 32 AF XY: 0.00146 AC XY: 109 AN XY: 74448

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00968

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00726

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000395 Hom.: 0

Bravo AF: 0.000393

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Woodhouse-Sakati syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.98
DANN	Benign	0.51

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: rs80336595; hg19: chr2-172290977;