rs121912288

Positions:

• chrX-154773152-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001363.5(DKC1):​c.1058C>T​(p.Ala353Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,085,387 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: DKC1 NM_001363.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:2
• Conservation: PhyloP100: 7.48

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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a mutagenesis_site Increases interaction with SHQ1. (size 0) in uniprot entity DKC1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DKC1. . Gene score misZ 3.3994 (greater than the threshold 3.09). GenCC has associacion of gene with Hoyeraal-Hreidarsson syndrome, DKC1-related disorder, dyskeratosis congenita, X-linked, dyskeratosis congenita.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant X-154773152-C-T is Pathogenic according to our data. Variant chrX-154773152-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154773152-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DKC1	NM_001363.5	c.1058C>T	p.Ala353Val	missense_variant	11/15	ENST00000369550.10	NP_001354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DKC1	ENST00000369550.10	c.1058C>T	p.Ala353Val	missense_variant	11/15	1	NM_001363.5	ENSP00000358563	P2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1085387 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 352545

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000241

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dyskeratosis congenita, X-linked Pathogenic:1 Other:2

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2009	- -

Dyskeratosis congenita Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 16, 2015	The p.A353V pathogenic mutation (also known as c.1058C>T), located in coding exon 11 of the DKC1 gene, results from a C to T substitution at nucleotide position 1058. The alanine at codon 353 is replaced by valine, an amino acid with similar properties. This common recurring mutation has been observed in patients with dyskeratosis congenita or Hoyeraal-Hreidarsson syndrome from disparate geographical locations, and its occurrence has been reported to be de novo in multiple cases. (Knight SW et al, Am. J. Hum. Genet. 1999 Jul; 65(1):50-8; Viprakasit V et al, Haematologica 2001 Aug; 86(8):871-2; Ding YG et al, J. Invest. Dermatol. 2004 Sep; 123(3):470-3; Borggraefe I et al, J. Pediatr. Gastroenterol. Nutr. 2009 Sep; Grozdanov PN et al, Hum. Mol. Genet. 2009 Dec; 18(23):4546-51; Tamhankar PM et al, Indian J Pediatr 2010 Mar; 77(3):310-2; Lai W et al, J. Dermatol. Sci. 2011 Aug; 63(2):122-4; 49(3):359-63). Based on the available evidence, the p.A353V is classified as a pathogenic mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 04, 2023	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DKC1 protein function. ClinVar contains an entry for this variant (Variation ID: 11587). This missense change has been observed in individual(s) with dyskeratosis congenita and it is known to be the most frequent cause of the disease (PMID: 10364516, 16332973, 19835419). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 353 of the DKC1 protein (p.Ala353Val). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects DKC1 function (PMID: 19391112, 19835419, 22058290, 25992652). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.74	.;D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.3	.;N
REVEL	Pathogenic	0.74
Sift	Benign	0.47	.;T
Sift4G	Benign	0.40	T;T
Polyphen		0.20	.;B
Vest4		0.74
MutPred		0.69		Gain of glycosylation at T352 (P = 0.2076);Gain of glycosylation at T352 (P = 0.2076);
MVP		1.0
MPC		2.2
ClinPred		0.92	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.96

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: rs121912288; hg19: chrX-154001427;