NM_001363.5:c.949C>T

Variant names:

• chrX-154770792-C-T
• rs121912290
• NM_001363.5:c.949C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001363.5(DKC1):​c.949C>T​(p.Leu317Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L317V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: DKC1 NM_001363.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:2
• Conservation: PhyloP100: 4.61
• Publications: 6 publications found

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]

DKC1 Gene-Disease associations (from GenCC):

• DKC1-related disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• dyskeratosis congenita, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• dyskeratosis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hoyeraal-Hreidarsson syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant X-154770792-C-T is Pathogenic according to our data. Variant chrX-154770792-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38957.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKC1	NM_001363.5	c.949C>T	p.Leu317Phe	missense_variant	Exon 10 of 15	ENST00000369550.10	NP_001354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKC1	ENST00000369550.10	c.949C>T	p.Leu317Phe	missense_variant	Exon 10 of 15	1	NM_001363.5	ENSP00000358563.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

Dyskeratosis congenita, X-linked Other:2

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UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dyskeratosis congenita Pathogenic:1

May 09, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L317F variant (also known as c.949C>T), located in coding exon 10 of the DKC1 gene, results from a C to T substitution at nucleotide position 949. The leucine at codon 317 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was reported in individual(s) with features consistent with DKC1-related dyskeratosis congenita (Rostamiani K et al. Blood Cells Mol Dis, 2010 Oct;44:88; Jonassaint NL et al. Aging Cell, 2013 Apr;12:319-23; Lauhasurayotin S et al. NPJ Genom Med, 2019 Dec;4:30; Schratz KE et al. Blood, 2020 May;135:1946-1956). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.5	H;H
PhyloP100		4.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.2	.;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.030	D;D
Polyphen		0.72	.;P
Vest4		0.75
MutPred		0.84		Gain of methylation at K314 (P = 0.1051);Gain of methylation at K314 (P = 0.1051);
MVP		0.99
MPC		2.6
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.98
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121912290; hg19: chrX-153999067;