X-154773133-A-C

Variant names:

• chrX-154773133-A-C
• rs1248744087
• NM_001363.5:c.1039A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001363.5(DKC1):​c.1039A>C​(p.Ile347Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000953 in 1,049,502 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. I347V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.5e-7 (0 hom. 0 hem.)
• Consequence: DKC1 NM_001363.5 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.80
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 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

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.1039A>C	p.Ile347Leu	missense splice_region	Exon 11 of 15	NP_001354.1	O60832-1
	DKC1	NM_001142463.3		c.1039A>C	p.Ile347Leu	missense splice_region	Exon 11 of 15	NP_001135935.1	A0A8Q3SIY6
	DKC1	NM_001288747.2		c.1039A>C	p.Ile347Leu	missense splice_region	Exon 11 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.1039A>C	p.Ile347Leu	missense splice_region	Exon 11 of 15	ENSP00000358563.5	O60832-1
	DKC1	ENST00000620277.4	TSL:1	n.1263A>C		splice_region non_coding_transcript_exon	Exon 11 of 14
	DKC1	ENST00000953351.1		c.1075A>C	p.Ile359Leu	missense splice_region	Exon 11 of 15	ENSP00000623410.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.53e-7 AC: 1 AN: 1049502 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 326106

African (AFR) AF: 0.0000392 AC: 1 AN: 25530

American (AMR) AF: 0.00 AC: 0 AN: 34957

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19032

East Asian (EAS) AF: 0.00 AC: 0 AN: 29960

South Asian (SAS) AF: 0.00 AC: 0 AN: 52813

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40389

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4031

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 798339

Other (OTH) AF: 0.00 AC: 0 AN: 44451

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Uncertain	0.77	D
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.8
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.36
Sift	Benign	0.045	D
Sift4G	Benign	0.28	T
Polyphen		0.0050	B
Vest4		0.36
MutPred		0.49		Loss of sheet (P = 0.0817)
MVP		0.96
MPC		1.3
ClinPred		0.87	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.92
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs1248744087; hg19: chrX-154001408;