Genetic Variant DKC1:p.Leu321Ile (chrX-154770804-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001363.5(DKC1):c.961C>A(p.Leu321Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L321V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Consequence

DKC1
NM_001363.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.62

Publications

5 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

DKC1-related disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
dyskeratosis congenita, X-linked
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
dyskeratosis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hoyeraal-Hreidarsson syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DKC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.835

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DKC1	NM_001363.5	MANE Select	c.961C>A	p.Leu321Ile	missense	Exon 10 of 15	NP_001354.1	O60832-1
DKC1	NM_001142463.3		c.961C>A	p.Leu321Ile	missense	Exon 10 of 15	NP_001135935.1	A0A8Q3SIY6
DKC1	NM_001288747.2		c.961C>A	p.Leu321Ile	missense	Exon 10 of 14	NP_001275676.1	O60832-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DKC1	ENST00000369550.10	TSL:1 MANE Select	c.961C>A	p.Leu321Ile	missense	Exon 10 of 15	ENSP00000358563.5	O60832-1
DKC1	ENST00000620277.4	TSL:1	n.1185C>A		non_coding_transcript_exon	Exon 10 of 14
DKC1	ENST00000953351.1		c.997C>A	p.Leu333Ile	missense	Exon 10 of 15	ENSP00000623410.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.84

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.5

PhyloP100

4.6

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.57

Sift

Uncertain

0.0080

Sift4G

Benign

0.12

Polyphen

0.79

Vest4

0.66

MutPred

0.63

Gain of catalytic residue at L321 (P = 0.0275)

MVP

0.95

MPC

2.6

ClinPred

0.98

GERP RS

5.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

3.7

Varity_R

0.80

gMVP

0.91

Mutation Taster

=13/87

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over