X-154762795-A-T

Variant summary

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

The ENST00000620277.4(DKC1):n.54A>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 555,725 control chromosomes in the GnomAD database, including 11 homozygotes. There are 646 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (3 hom., 69 hem., cov: 24)
  • Exomes 𝑓: 0.0025 (8 hom. 577 hem.)
• Consequence: DKC1 ENST00000620277.4 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.533

Genes affected

DKC1 (HGNC:2890): (dyskerin pseudouridine synthase 1) This gene functions in two distinct complexes. It plays an active role in telomerase stabilization and maintenance, as well as recognition of snoRNAs containing H/ACA sequences which provides stability during biogenesis and assembly into H/ACA small nucleolar RNA ribonucleoproteins (snoRNPs). This gene is highly conserved and widely expressed, and may play additional roles in nucleo-cytoplasmic shuttling, DNA damage response, and cell adhesion. Mutations have been associated with X-linked dyskeratosis congenita. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00139 (158/113284) while in subpopulation SAS AF= 0.0361 (102/2824). AF 95% confidence interval is 0.0304. There are 3 homozygotes in gnomad4. There are 69 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DKC1	ENST00000620277.4	n.54A>T		non_coding_transcript_exon_variant	1/14	1
DKC1	ENST00000413910.6	c.-171A>T		5_prime_UTR_variant, NMD_transcript_variant	1/16	5
DKC1	ENST00000426673.6	c.-171A>T		5_prime_UTR_variant, NMD_transcript_variant	1/15	5

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 157 AN: 113235 Hom.: 3 Cov.: 24 AF XY: 0.00192 AC XY: 68 AN XY: 35403

Gnomad AFR AF: 0.000192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000920

Gnomad ASJ AF: 0.00150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000844

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00249 AC: 1102 AN: 442441 Hom.: 8 Cov.: 6 AF XY: 0.00456 AC XY: 577 AN XY: 126665

Gnomad4 AFR exome AF: 0.0000888

Gnomad4 AMR exome AF: 0.000105

Gnomad4 ASJ exome AF: 0.00326

Gnomad4 EAS exome AF: 0.000134

Gnomad4 SAS exome AF: 0.0277

Gnomad4 FIN exome AF: 0.000222

Gnomad4 NFE exome AF: 0.000551

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00139 AC: 158 AN: 113284 Hom.: 3 Cov.: 24 AF XY: 0.00195 AC XY: 69 AN XY: 35462

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.0000919

Gnomad4 ASJ AF: 0.00150

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0361

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000844

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000486 Hom.: 3

Bravo AF: 0.000631

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 06, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	9.2
Dann	Benign	0.72

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: rs782519189; hg19: chrX-153991070;