rs1127051

Positions:

• chrX-154776309-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001363.5(DKC1):​c.1461C>T​(p.Ala487=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0621 in 1,193,942 control chromosomes in the GnomAD database, including 1,815 homozygotes. There are 22,899 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (273 hom., 2194 hem., cov: 23)
  • Exomes 𝑓: 0.061 (1542 hom. 20705 hem.)
• Consequence: DKC1 NM_001363.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.809

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant X-154776309-C-T is Benign according to our data. Variant chrX-154776309-C-T is described in ClinVar as [Benign]. Clinvar id is 128896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154776309-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.809 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DKC1	NM_001363.5	c.1461C>T	p.Ala487=	synonymous_variant	14/15	ENST00000369550.10	NP_001354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DKC1	ENST00000369550.10	c.1461C>T	p.Ala487=	synonymous_variant	14/15	1	NM_001363.5	ENSP00000358563	P2

Frequencies

GnomAD3 genomes AF: 0.0722 AC: 8075 AN: 111859 Hom.: 273 Cov.: 23 AF XY: 0.0641 AC XY: 2186 AN XY: 34079

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0484

Gnomad ASJ AF: 0.0272

Gnomad EAS AF: 0.0363

Gnomad SAS AF: 0.00443

Gnomad FIN AF: 0.0392

Gnomad MID AF: 0.0294

Gnomad NFE AF: 0.0628

Gnomad OTH AF: 0.0596

GnomAD3 exomes AF: 0.0522 AC: 7864 AN: 150590 Hom.: 209 AF XY: 0.0464 AC XY: 2160 AN XY: 46550

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0323

Gnomad ASJ exome AF: 0.0286

Gnomad EAS exome AF: 0.0450

Gnomad SAS exome AF: 0.00459

Gnomad FIN exome AF: 0.0421

Gnomad NFE exome AF: 0.0649

Gnomad OTH exome AF: 0.0512

GnomAD4 exome AF: 0.0610 AC: 66020 AN: 1082032 Hom.: 1542 Cov.: 31 AF XY: 0.0588 AC XY: 20705 AN XY: 352114

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.0341

Gnomad4 ASJ exome AF: 0.0286

Gnomad4 EAS exome AF: 0.0467

Gnomad4 SAS exome AF: 0.00556

Gnomad4 FIN exome AF: 0.0463

Gnomad4 NFE exome AF: 0.0661

Gnomad4 OTH exome AF: 0.0562

GnomAD4 genome AF: 0.0722 AC: 8084 AN: 111910 Hom.: 273 Cov.: 23 AF XY: 0.0643 AC XY: 2194 AN XY: 34140

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.0484

Gnomad4 ASJ AF: 0.0272

Gnomad4 EAS AF: 0.0369

Gnomad4 SAS AF: 0.00444

Gnomad4 FIN AF: 0.0392

Gnomad4 NFE AF: 0.0628

Gnomad4 OTH AF: 0.0588

Alfa AF: 0.0604 Hom.: 1177

Bravo AF: 0.0768

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Dyskeratosis congenita Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 24, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	2.0
DANN	Benign	0.74
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs1127051; hg19: chrX-154004584; COSMIC: COSV65729532; COSMIC: COSV65729532;