X-154762795-A-T

Variant names:

• chrX-154762795-A-T
• rs782519189
• ENST00000620277.4:n.54A>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000620277.4(DKC1):​n.54A>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 555,725 control chromosomes in the GnomAD database, including 11 homozygotes. There are 646 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (3 hom., 69 hem., cov: 24)
  • Exomes 𝑓: 0.0025 (8 hom. 577 hem.)
• Consequence: DKC1 ENST00000620277.4 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.533
• 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: 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

ENSG00000307948 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00139 (158/113284) while in subpopulation SAS AF = 0.0361 (102/2824). AF 95% confidence interval is 0.0304. There are 3 homozygotes in GnomAd4. There are 69 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 158 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKC1	NM_001363.5	c.-171A>T		upstream_gene_variant		ENST00000369550.10	NP_001354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKC1	ENST00000369550.10	c.-171A>T		upstream_gene_variant		1	NM_001363.5	ENSP00000358563.5

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 157 AN: 113235 Hom.: 3 Cov.: 24

Gnomad AFR AF: 0.000192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000920

Gnomad ASJ AF: 0.00150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000844

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00249 AC: 1102 AN: 442441 Hom.: 8 Cov.: 6 AF XY: 0.00456 AC XY: 577 AN XY: 126665

African (AFR) AF: 0.0000888 AC: 1 AN: 11264

American (AMR) AF: 0.000105 AC: 2 AN: 19031

Ashkenazi Jewish (ASJ) AF: 0.00326 AC: 36 AN: 11036

East Asian (EAS) AF: 0.000134 AC: 3 AN: 22345

South Asian (SAS) AF: 0.0277 AC: 847 AN: 30597

European-Finnish (FIN) AF: 0.000222 AC: 6 AN: 26991

Middle Eastern (MID) AF: 0.00209 AC: 4 AN: 1914

European-Non Finnish (NFE) AF: 0.000551 AC: 163 AN: 295901

Other (OTH) AF: 0.00171 AC: 40 AN: 23362

GnomAD4 genome AF: 0.00139 AC: 158 AN: 113284 Hom.: 3 Cov.: 24 AF XY: 0.00195 AC XY: 69 AN XY: 35462

African (AFR) AF: 0.000192 AC: 6 AN: 31316

American (AMR) AF: 0.0000919 AC: 1 AN: 10886

Ashkenazi Jewish (ASJ) AF: 0.00150 AC: 4 AN: 2660

East Asian (EAS) AF: 0.00 AC: 0 AN: 3569

South Asian (SAS) AF: 0.0361 AC: 102 AN: 2824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6277

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000844 AC: 45 AN: 53294

Other (OTH) AF: 0.00 AC: 0 AN: 1555

Alfa AF: 0.000486 Hom.: 3

Bravo AF: 0.000631

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 06, 2018

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.2
DANN	Benign	0.72
PhyloP100		0.53
PromoterAI		0.16	Neutral
Mutation Taster		=300/0	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: rs782519189; hg19: chrX-153991070;