chrX-154773152-C-T

Variant names:

• chrX-154773152-C-T
• rs121912288
• NM_001363.5:c.1058C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A353A) has been classified as Likely benign.

• 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:4 O:2
• Conservation: PhyloP100: 7.48
• Publications: 70 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: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 11587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKC1	NM_001363.5	MANE Select	c.1058C>T	p.Ala353Val	missense	Exon 11 of 15	NP_001354.1
	DKC1	NM_001142463.3		c.1058C>T	p.Ala353Val	missense	Exon 11 of 15	NP_001135935.1
	DKC1	NM_001288747.2		c.1058C>T	p.Ala353Val	missense	Exon 11 of 14	NP_001275676.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKC1	ENST00000369550.10	TSL:1 MANE Select	c.1058C>T	p.Ala353Val	missense	Exon 11 of 15	ENSP00000358563.5
	DKC1	ENST00000620277.4	TSL:1	n.1282C>T		non_coding_transcript_exon	Exon 11 of 14
	DKC1	ENST00000696575.1		c.1058C>T	p.Ala353Val	missense	Exon 11 of 15	ENSP00000512730.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00 AC: 0 AN: 183228 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 26178

American (AMR) AF: 0.00 AC: 0 AN: 35165

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19290

East Asian (EAS) AF: 0.00 AC: 0 AN: 30145

South Asian (SAS) AF: 0.00 AC: 0 AN: 53760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4106

European-Non Finnish (NFE) AF: 0.00000241 AC: 2 AN: 830621

Other (OTH) AF: 0.00 AC: 0 AN: 45648

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Dec 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Dyskeratosis congenita Pathogenic:2

Jul 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 11587). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects DKC1 function (PMID: 19391112, 19835419, 22058290, 25992652). For these reasons, this variant has been classified as Pathogenic.

Nov 16, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Pathogenic:1

Apr 28, 2023

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the DKC1 gene demonstrated a sequence change, c.1058C>T, in exon 11 that results in an amino acid change, p.Ala353Val. The p.Ala353Val change affects a highly conserved amino acid residue located in a domain of the DKC1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala353Val substitution. This sequence change has previously been described in individuals with dyskeratosis congenita (DC)/ Hoyeraal-Hreidarsson syndrome and accounts for majority of cases with DC (PMID: 16332973, 10700698, 10364516, 31269755). Functional studies indicate that this sequence change has an impact on DKC1 function (PMID: 19391112, 19835419, 22058290, 25992652). These collective evidences indicate that this sequence change is pathogenic.

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.7	L
PhyloP100		7.5
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.74
Sift	Benign	0.47	T
Sift4G	Benign	0.40	T
Polyphen		0.20	B
Vest4		0.74
MutPred		0.69		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
Mutation Taster		=28/72	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121912288; hg19: chrX-154001427;