rs1800533

Variant names:

• chrX-154776873-G-A
• rs1800533
• NM_001363.5:c.*6G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-154776873-G-A
• chrX-154776873-G-C
• chrX-154776873-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001363.5(DKC1):​c.*6G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,182,442 control chromosomes in the GnomAD database, including 5,806 homozygotes. There are 44,397 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (516 hom., 3149 hem., cov: 23)
  • Exomes 𝑓: 0.11 (5290 hom. 41248 hem.)
• Consequence: DKC1 NM_001363.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.43
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant X-154776873-G-A is Benign according to our data. Variant chrX-154776873-G-A is described in ClinVar as Benign. ClinVar VariationId is 166995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

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.*6G>A		3_prime_UTR	Exon 15 of 15	NP_001354.1	O60832-1
	DKC1	NM_001142463.3		c.*6G>A		3_prime_UTR	Exon 15 of 15	NP_001135935.1	A0A8Q3SIY6
	DKC1	NM_001288747.2		c.*777G>A		3_prime_UTR	Exon 14 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.*6G>A		3_prime_UTR	Exon 15 of 15	ENSP00000358563.5	O60832-1
	DKC1	ENST00000620277.4	TSL:1	n.2264G>A		non_coding_transcript_exon	Exon 14 of 14
	DKC1	ENST00000953351.1		c.*6G>A		3_prime_UTR	Exon 15 of 15	ENSP00000623410.1

Frequencies

GnomAD3 genomes AF: 0.0916 AC: 10180 AN: 111102 Hom.: 516 Cov.: 23

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.0606

Gnomad MID AF: 0.148

Gnomad NFE AF: 0.0927

Gnomad OTH AF: 0.118

GnomAD2 exomes AF: 0.147 AC: 23600 AN: 161034 AF XY: 0.163

Gnomad AFR exome AF: 0.0263

Gnomad AMR exome AF: 0.259

Gnomad ASJ exome AF: 0.192

Gnomad EAS exome AF: 0.101

Gnomad FIN exome AF: 0.0673

Gnomad NFE exome AF: 0.0950

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.109 AC: 116583 AN: 1071289 Hom.: 5290 Cov.: 26 AF XY: 0.121 AC XY: 41248 AN XY: 340227

African (AFR) AF: 0.0247 AC: 641 AN: 25915

American (AMR) AF: 0.249 AC: 8371 AN: 33639

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 3702 AN: 19004

East Asian (EAS) AF: 0.0641 AC: 1906 AN: 29713

South Asian (SAS) AF: 0.358 AC: 18787 AN: 52477

European-Finnish (FIN) AF: 0.0699 AC: 2776 AN: 39737

Middle Eastern (MID) AF: 0.245 AC: 997 AN: 4074

European-Non Finnish (NFE) AF: 0.0896 AC: 73631 AN: 821591

Other (OTH) AF: 0.128 AC: 5772 AN: 45139

GnomAD4 genome AF: 0.0915 AC: 10172 AN: 111153 Hom.: 516 Cov.: 23 AF XY: 0.0944 AC XY: 3149 AN XY: 33365

African (AFR) AF: 0.0271 AC: 830 AN: 30631

American (AMR) AF: 0.190 AC: 1995 AN: 10482

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 512 AN: 2643

East Asian (EAS) AF: 0.102 AC: 362 AN: 3548

South Asian (SAS) AF: 0.366 AC: 919 AN: 2509

European-Finnish (FIN) AF: 0.0606 AC: 366 AN: 6044

Middle Eastern (MID) AF: 0.139 AC: 30 AN: 216

European-Non Finnish (NFE) AF: 0.0927 AC: 4905 AN: 52891

Other (OTH) AF: 0.116 AC: 176 AN: 1517

Alfa AF: 0.0966 Hom.: 1459

Bravo AF: 0.0954

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Dyskeratosis congenita, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.17
DANN	Benign	0.59
PhyloP100		-1.4
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs1800533; hg19: chrX-154005148; COSMIC: COSV65729427; COSMIC: COSV65729427;