rs1814542779

Variant names:

• chrX-154764883-G-A
• rs1814542779
• NM_001363.5:c.17-16G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-154764883-G-A
• chrX-154764883-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001363.5(DKC1):​c.17-16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000892 in 112,074 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 9.4e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: DKC1 NM_001363.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.68
• 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), G2P, ClinGen
• dyskeratosis congenita

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-154764883-G-A is Benign according to our data. Variant chrX-154764883-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2791264.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.17-16G>A		intron	N/A	NP_001354.1	O60832-1
	DKC1	NM_001142463.3		c.17-16G>A		intron	N/A	NP_001135935.1	A0A8Q3SIY6
	DKC1	NM_001288747.2		c.17-16G>A		intron	N/A	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.17-16G>A		intron	N/A	ENSP00000358563.5	O60832-1
	DKC1	ENST00000620277.4	TSL:1	n.241-16G>A		intron	N/A
	DKC1	ENST00000696588.1		c.-1086G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 13	ENSP00000513251.1	A0A8V8TKY9

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112074 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000655

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.40e-7 AC: 1 AN: 1063827 Hom.: 0 Cov.: 25 AF XY: 0.00000298 AC XY: 1 AN XY: 335813

African (AFR) AF: 0.00 AC: 0 AN: 25767

American (AMR) AF: 0.00 AC: 0 AN: 35150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19133

East Asian (EAS) AF: 0.00 AC: 0 AN: 30058

South Asian (SAS) AF: 0.0000188 AC: 1 AN: 53330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4052

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 810902

Other (OTH) AF: 0.00 AC: 0 AN: 44983

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112074 Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1 AN XY: 34290

African (AFR) AF: 0.00 AC: 0 AN: 30793

American (AMR) AF: 0.00 AC: 0 AN: 10559

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3618

South Asian (SAS) AF: 0.00 AC: 0 AN: 2764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53226

Other (OTH) AF: 0.000655 AC: 1 AN: 1526

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Dyskeratosis congenita (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.024
DANN	Benign	0.73
PhyloP100		-2.7
PromoterAI		-0.027	Neutral

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: rs1814542779; hg19: chrX-153993158;