rs121912305
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5
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
NM_001363.5 missense
Scores
7
3
3
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, DKC1
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: {not_provided=2, Uncertain_significance=1, Likely_pathogenic=1}. Variant chrX-154766313-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DKC1 | NM_001363.5 | c.361A>G | p.Ser121Gly | missense_variant | 5/15 | ENST00000369550.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DKC1 | ENST00000369550.10 | c.361A>G | p.Ser121Gly | missense_variant | 5/15 | 1 | NM_001363.5 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 37
GnomAD4 exome
Cov.:
37
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1Other:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Dyskeratosis congenita, X-linked Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2009 | - - |
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
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 | Invitae | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;.
MutationTaster
Benign
A
PrimateAI
Pathogenic
D
Sift4G
Benign
T;T;T
Polyphen
0.56
.;P;.
Vest4
MutPred
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
MPC
1.7
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at