NM_001363.5:c.109_111delCTT

Variant names:

• chrX-154765465-TTTC-T
• rs137854489
• NM_001363.5:c.109_111delCTT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 PM1 PM2 PM4_Supporting PP5_Moderate

The NM_001363.5(DKC1):​c.109_111delCTT​(p.Leu37del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000755811: Experimental studies have shown that this in-frame deletion results in compromised telomere maintenance, characterized by shortened telomeres and reduced telomerase activity (PMID:22058290, 23660516, 21602826, 25992652).".

• Frequency: Genomes: not found (cov: 23)
• Consequence: DKC1 NM_001363.5 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.27
• Publications: 16 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: 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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000755811: Experimental studies have shown that this in-frame deletion results in compromised telomere maintenance, characterized by shortened telomeres and reduced telomerase activity (PMID: 22058290, 23660516, 21602826, 25992652).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001363.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001363.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant X-154765465-TTTC-T is Pathogenic according to our data. Variant chrX-154765465-TTTC-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 11583.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKC1	NM_001363.5	MANE Select	c.109_111delCTT	p.Leu37del	conservative_inframe_deletion	Exon 3 of 15	NP_001354.1	O60832-1
	DKC1	NM_001142463.3		c.109_111delCTT	p.Leu37del	conservative_inframe_deletion	Exon 3 of 15	NP_001135935.1	A0A8Q3SIY6
	DKC1	NM_001288747.2		c.109_111delCTT	p.Leu37del	conservative_inframe_deletion	Exon 3 of 14	NP_001275676.1	O60832-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKC1	ENST00000369550.10	TSL:1 MANE Select	c.109_111delCTT	p.Leu37del	conservative_inframe_deletion	Exon 3 of 15	ENSP00000358563.5	O60832-1
	DKC1	ENST00000620277.4	TSL:1	n.333_335delCTT		non_coding_transcript_exon	Exon 3 of 14
	DKC1	ENST00000953351.1		c.109_111delCTT	p.Leu37del	conservative_inframe_deletion	Exon 3 of 15	ENSP00000623410.1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=64/36	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137854489; hg19: chrX-153993740;