chrX-154762892-G-A

Variant names:

• chrX-154762892-G-A
• rs782436792
• NM_001363.5:c.-74G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.173
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS2: High AC in GnomAd4 at 44 XL,AD gene.

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.-74G>A		5_prime_UTR	Exon 1 of 15	NP_001354.1
	DKC1	NM_001142463.3		c.-74G>A		5_prime_UTR	Exon 1 of 15	NP_001135935.1
	DKC1	NM_001288747.2		c.-74G>A		5_prime_UTR	Exon 1 of 14	NP_001275676.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKC1	ENST00000369550.10	TSL:1 MANE Select	c.-74G>A		5_prime_UTR	Exon 1 of 15	ENSP00000358563.5
	DKC1	ENST00000620277.4	TSL:1	n.151G>A		non_coding_transcript_exon	Exon 1 of 14
	DKC1	ENST00000953351.1		c.-74G>A		5_prime_UTR	Exon 1 of 15	ENSP00000623410.1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 44 AN: 113544 Hom.: 0 Cov.: 26

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.: 0 Cov.: 25 AF XY: 0.000168 AC XY: 54 AN XY: 321870

African (AFR) AF: 0.00 AC: 0 AN: 24481

American (AMR) AF: 0.000323 AC: 9 AN: 27863

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18398

East Asian (EAS) AF: 0.00 AC: 0 AN: 27026

South Asian (SAS) AF: 0.00 AC: 0 AN: 49258

European-Finnish (FIN) AF: 0.0000269 AC: 1 AN: 37214

Middle Eastern (MID) AF: 0.000497 AC: 2 AN: 4023

European-Non Finnish (NFE) AF: 0.000209 AC: 166 AN: 795416

Other (OTH) AF: 0.000345 AC: 15 AN: 43425

GnomAD4 genome AF: 0.000387 AC: 44 AN: 113596 Hom.: 0 Cov.: 26 AF XY: 0.000308 AC XY: 11 AN XY: 35760

African (AFR) AF: 0.0000637 AC: 2 AN: 31417

American (AMR) AF: 0.00184 AC: 20 AN: 10895

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3583

South Asian (SAS) AF: 0.00 AC: 0 AN: 2859

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6369

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000412 AC: 22 AN: 53357

Other (OTH) AF: 0.00 AC: 0 AN: 1564

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.000567

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.5
DANN	Benign	0.85
PhyloP100		-0.17
PromoterAI		0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs782436792; hg19: chrX-153991167;