rs1248744087

Positions:

• chrX-154773133-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_001363.5(DKC1):​c.1039A>G​(p.Ile347Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: DKC1 NM_001363.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001363.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DKC1. . Gene score misZ 3.3994 (greater than the threshold 3.09). GenCC has associacion of gene with Hoyeraal-Hreidarsson syndrome, DKC1-related disorder, dyskeratosis congenita, X-linked, dyskeratosis congenita.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33919013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DKC1	NM_001363.5	c.1039A>G	p.Ile347Val	missense_variant, splice_region_variant	11/15	ENST00000369550.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DKC1	ENST00000369550.10	c.1039A>G	p.Ile347Val	missense_variant, splice_region_variant	11/15	1	NM_001363.5	P2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dyskeratosis congenita Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2017

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DKC1-related disease. This sequence change replaces isoleucine with valine at codon 347 of the DKC1 protein (p.Ile347Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Uncertain	0.52	.;D
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.64	.;N
REVEL	Uncertain	0.32
Sift	Benign	0.14	.;T
Sift4G	Benign	0.39	T;T
Polyphen		0.011	.;B
Vest4		0.13
MutPred		0.54		Gain of catalytic residue at I347 (P = 0.0468);Gain of catalytic residue at I347 (P = 0.0468);
MVP		0.90
MPC		1.1
ClinPred		0.38	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.78

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: rs1248744087; hg19: chrX-154001408;