Genetic Variant DKC1:n.151G>A (chrX-154762892-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001363.5(DKC1):c.-74G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,140,700 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 65 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 0.00039 ( 0 hom., 11 hem., cov: 26)

Exomes 𝑓: 0.00019 ( 0 hom. 54 hem. )

Consequence

DKC1
NM_001363.5 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.173

Publications

0 publications found

Variant links:

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

DKC1 links:

ENSG00000307948 (HGNC:):

ENSG00000307948 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BS2

High AC in GnomAd4 at 44 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKC1	NM_001363.5 link	c.-74G>A		5_prime_UTR_variant	Exon 1 of 15	ENST00000369550.10	NP_001354.1	O60832-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKC1	ENST00000369550.10 link	c.-74G>A		5_prime_UTR_variant	Exon 1 of 15	1	NM_001363.5	ENSP00000358563.5		O60832-1

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

113544

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000638

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00184

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:

0.000412

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000188

AC:

193

AN:

1027104

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

AN XY:

321870

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24481

American (AMR)

AF:

0.000323

AC:

AN:

27863

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18398

East Asian (EAS)

AF:

0.00

AC:

AN:

27026

South Asian (SAS)

AF:

0.00

AC:

AN:

49258

European-Finnish (FIN)

AF:

0.0000269

AC:

AN:

37214

Middle Eastern (MID)

AF:

0.000497

AC:

AN:

4023

European-Non Finnish (NFE)

AF:

0.000209

AC:

166

AN:

795416

Other (OTH)

AF:

0.000345

AC:

AN:

43425

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000387

AC:

AN:

113596

Hom.:

Cov.:

AF XY:

0.000308

AC XY:

AN XY:

35760

show subpopulations

African (AFR)

AF:

0.0000637

AC:

AN:

31417

American (AMR)

AF:

0.00184

AC:

AN:

10895

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3583

South Asian (SAS)

AF:

0.00

AC:

AN:

2859

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6369

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

53357

Other (OTH)

AF:

0.00

AC:

AN:

1564

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000567

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 13, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

5.5

(source)

DANN

Benign

0.85

PhyloP100

-0.17

PromoterAI

0.026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=300/0

polymorphism

(source)

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

Publications

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X-154762892-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over