rs121912305

Positions:

• chrX-154766313-A-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.361A>G​(p.Ser121Gly) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: DKC1 NM_001363.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O:2
• Conservation: PhyloP100: 8.79

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 (HGNC:):

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 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant X-154766313-A-G is Pathogenic according to our data. Variant chrX-154766313-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 11592.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=2, Likely_pathogenic=2}. Variant chrX-154766313-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DKC1	NM_001363.5	c.361A>G	p.Ser121Gly	missense_variant	5/15	ENST00000369550.10	NP_001354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DKC1	ENST00000369550.10	c.361A>G	p.Ser121Gly	missense_variant	5/15	1	NM_001363.5	ENSP00000358563.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2009	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with X-linked dyskeratosis congenita (MIM#305000). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Hoyeraal-Hreidarsson syndrome is described as the clinically severe form of dyskeratosis congenita and p.(Ala353Val) has been reported in both (PMID: 25940403). In addition, it has been found that severity of dyskeratosis congenita correlates with telomere length (PMID: 16332973). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to glycine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and very high conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Ser121Arg) waa identified in an individual from agranulocytosis and aplastic anaemia cohort however, its germline origin was not confirmed (PMID: 26360549). (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in two brothers with Hoyeraal-Hreidarsson syndrome (PMID: 10583221), a teenage boy with aplastic anaemia and no other features (PMID: 31027506). In addition, it has been reported twice in ClinVar by diagnostics laboratories with confirmed phenotypes of pancytopaenia, bone marrow aplasia with a confirmed diagnosis of DKC and bone marrow failure, leukoplakia, microcephaly, and developmental delay. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is inconclusive. In vitro assays have found that this variant had no impact on binding of SHQ1, an assembly factor for telomerases. However, this is unsurprising as this variant lies within the catalytic domain of DKC1 protein (PMID: 19734544). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 19, 2016

The S121G variant in the DKC1 gene has been reported in two brothers with a diagnosis of Hoyeraal-Hreidarsson syndrome (Knight et al., 2009; Aalfs et al., 1995). The S121G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S121G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the protein's catalytic domain that is conserved across species (Vuilliamy et al., 2008). In silico analysis predicts this variant is probably damaging to the protein structure/function. The S121G variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Dyskeratosis congenita Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 03, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with Hoyeraal-Hreidarsson syndrome and with clinical features of DKC1-related disease (PMID: 10583221, 31027506). ClinVar contains an entry for this variant (Variation ID: 11592). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with glycine at codon 121 of the DKC1 protein (p.Ser121Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. -

Hoyeraal-Hreidarsson syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	.;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.4	L;L;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.5	.;D;D
REVEL	Pathogenic	0.73
Sift	Benign	0.13	.;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.56	.;P;.
Vest4		0.61
MutPred		0.80		Loss of glycosylation at S121 (P = 0.0176);Loss of glycosylation at S121 (P = 0.0176);Loss of glycosylation at S121 (P = 0.0176);
MVP		1.0
MPC		1.7
ClinPred		0.88	D
GERP RS		6.0
Varity_R		0.70
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs121912305; hg19: chrX-153994588;