rs1114167422

Variant names:

• chrX-154773148-A-G
• rs1114167422
• NM_001363.5:c.1054A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_001363.5(DKC1):​c.1054A>G​(p.Thr352Ala) 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 (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: DKC1 NM_001363.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.84

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the DKC1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 27 curated benign missense variants. Gene score misZ: 3.3994 (above the threshold of 3.09). GenCC associations: The gene is linked to Hoyeraal-Hreidarsson syndrome, DKC1-related disorder, dyskeratosis congenita, X-linked, dyskeratosis congenita.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• PP5: Variant X-154773148-A-G is Pathogenic according to our data. Variant chrX-154773148-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 427887.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKC1	NM_001363.5	c.1054A>G	p.Thr352Ala	missense_variant	Exon 11 of 15	ENST00000369550.10	NP_001354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKC1	ENST00000369550.10	c.1054A>G	p.Thr352Ala	missense_variant	Exon 11 of 15	1	NM_001363.5	ENSP00000358563.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Dyskeratosis congenita, X-linked Pathogenic:1

-

Human Genetics Unit, University Of Colombo

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

A 31-year-old male from Udupiddy Jaffna, in the Northern Province of Sri Lanka had a history of recurrent febrile episodes which resolved spontaneously over the preceding two months. He is a product of a non-consanguineous marriage. Several of his male relatives, including two maternal uncles and three maternal cousins were affected with a similar type of condition. Clinical diagnosis of DKC was made based on the classical features of presentation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	.;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	2.0	M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.4	.;D
REVEL	Pathogenic	0.71
Sift	Benign	0.097	.;T
Sift4G	Benign	0.14	T;T
Polyphen		0.10	.;B
Vest4		0.69
MutPred		0.51		Loss of glycosylation at T352 (P = 0.0666);Loss of glycosylation at T352 (P = 0.0666);
MVP		0.99
MPC		2.2
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.68
gMVP		0.98

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: rs1114167422; hg19: chrX-154001423;