X-154762970-C-T

Variant names:

• chrX-154762970-C-T
• rs121912303
• NM_001363.5:c.5C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001363.5(DKC1):​c.5C>T​(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: DKC1 NM_001363.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:2
• Conservation: PhyloP100: 1.78
• Publications: 5 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

ENSG00000307948 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a modified_residue N-acetylalanine (size 0) in uniprot entity DKC1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853
• PP5: Variant X-154762970-C-T is Pathogenic according to our data. Variant chrX-154762970-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38951.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKC1	NM_001363.5	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 15	ENST00000369550.10	NP_001354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKC1	ENST00000369550.10	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 15	1	NM_001363.5	ENSP00000358563.5

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1068799 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 347697

African (AFR) AF: 0.00 AC: 0 AN: 25728

American (AMR) AF: 0.00 AC: 0 AN: 30775

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18805

East Asian (EAS) AF: 0.00 AC: 0 AN: 28574

South Asian (SAS) AF: 0.00 AC: 0 AN: 50837

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38159

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4099

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 826914

Other (OTH) AF: 0.00 AC: 0 AN: 44908

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 23, 2023

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.66). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with DKC1 related disorder (ClinVar ID: VCV000038951 / PMID: 10364516). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -

Dyskeratosis congenita Pathogenic:1

Apr 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects DKC1 function (PMID: 26571381). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 38951). This missense change has been observed in individuals with dyskeratosis congenita, bone marrow failure (PMID: 10364516, 11641517, 22664374, 33718801). 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 2 of the DKC1 protein (p.Ala2Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T;.
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.60	T;T;T
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.1	M;M;.
PhyloP100		1.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.0	.;N;N
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.69
MutPred		0.70		Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.98
MPC		1.4
ClinPred		0.86	D
GERP RS		3.9
PromoterAI		-0.45	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.76
Mutation Taster		=26/74	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: rs121912303; hg19: chrX-153991245;