rs121912297

chrX-154765931-A-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001363.5(DKC1):c.196A>G(p.Thr66Ala) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T66I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: DKC1 NM_001363.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:2
• Conservation: PhyloP100: 8.88

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 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001363.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154765932-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2579111.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, DKC1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant X-154765931-A-G is Pathogenic according to our data. Variant chrX-154765931-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154765931-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DKC1	NM_001363.5	c.196A>G	p.Thr66Ala	missense_variant	4/15	ENST00000369550.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DKC1	ENST00000369550.10	c.196A>G	p.Thr66Ala	missense_variant	4/15	1	NM_001363.5	P2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dyskeratosis congenita, X-linked Other:2

not provided, no classification provided	literature only	GeneReviews	-	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 04, 2019

Published functional studies demonstrate that T66A leads to lowered levels of rRNA seudouridylation as well as an increase in cell apoptosis (Montanaro et al., 2002; Bellodi et al., 2013); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10364516, 30577491, 21228398, 11851894, 23707062, 9888995, 22117216) -

Dyskeratosis congenita Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 17, 2023

This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 38946). This missense change has been observed in individual(s) with dyskeratosis congenita (PMID: 768476, 9888995). It has also been observed to segregate with disease in related individuals. This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 66 of the DKC1 protein (p.Thr66Ala). 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: 10591218, 16690864, 18212040, 23707062, 26571381, 30202881). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Uncertain	24
Dann	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.9	M;M;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.72	T
Sift4G	Uncertain	0.034	D;D;D
Polyphen		0.29	.;B;.
Vest4		0.76
MutPred		0.73		Loss of glycosylation at T66 (P = 0.0375);Loss of glycosylation at T66 (P = 0.0375);Loss of glycosylation at T66 (P = 0.0375);
MVP		1.0
MPC		2.2
ClinPred		0.98	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.58
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: rs121912297; hg19: chrX-153994206;