rs137854491

Variant names:

• chrX-154765450-C-A
• rs137854491
• NM_001363.5:c.91C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-154765450-C-A
• chrX-154765450-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_001363.5(DKC1):​c.91C>A​(p.Gln31Lys) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q31E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: DKC1 NM_001363.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.17
• Publications: 8 publications found

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: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• dyskeratosis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hoyeraal-Hreidarsson syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001363.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77
• PP5: Variant X-154765450-C-A is Pathogenic according to our data. Variant chrX-154765450-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11594.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKC1	NM_001363.5	MANE Select	c.91C>A	p.Gln31Lys	missense	Exon 3 of 15	NP_001354.1
	DKC1	NM_001142463.3		c.91C>A	p.Gln31Lys	missense	Exon 3 of 15	NP_001135935.1
	DKC1	NM_001288747.2		c.91C>A	p.Gln31Lys	missense	Exon 3 of 14	NP_001275676.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKC1	ENST00000369550.10	TSL:1 MANE Select	c.91C>A	p.Gln31Lys	missense	Exon 3 of 15	ENSP00000358563.5
	DKC1	ENST00000620277.4	TSL:1	n.315C>A		non_coding_transcript_exon	Exon 3 of 14
	DKC1	ENST00000696575.1		c.91C>A	p.Gln31Lys	missense	Exon 3 of 15	ENSP00000512730.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Dyskeratosis congenita, X-linked (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.41	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.028	D
Sift4G	Benign	0.11	T
Polyphen		0.10	B
Vest4		0.78
MutPred		0.48		Gain of ubiquitination at Q31 (P = 0.0045)
MVP		1.0
MPC		1.8
ClinPred		0.89	D
GERP RS		4.1
Varity_R		0.43
gMVP		0.94
Mutation Taster		=35/65	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137854491; hg19: chrX-153993725;