X-154766321-G-T

Variant names:

• chrX-154766321-G-T
• rs2728532
• NM_001363.5:c.369G>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001363.5(DKC1):​c.369G>T​(p.Thr123Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (38257 hom., 30401 hem., cov: 20)
  • Exomes 𝑓: 1.0 (366695 hom. 363283 hem.)
  • Failed GnomAD Quality Control
• Consequence: DKC1 NM_001363.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.53
• Publications: 20 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.012).
• BP6: Variant X-154766321-G-T is Benign according to our data. Variant chrX-154766321-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 166994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.53 with no splicing effect.

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.369G>T	p.Thr123Thr	synonymous	Exon 5 of 15	NP_001354.1	O60832-1
	DKC1	NM_001142463.3		c.369G>T	p.Thr123Thr	synonymous	Exon 5 of 15	NP_001135935.1	A0A8Q3SIY6
	DKC1	NM_001288747.2		c.369G>T	p.Thr123Thr	synonymous	Exon 5 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.369G>T	p.Thr123Thr	synonymous	Exon 5 of 15	ENSP00000358563.5	O60832-1
	DKC1	ENST00000620277.4	TSL:1	n.593G>T		non_coding_transcript_exon	Exon 5 of 14
	DKC1	ENST00000953351.1		c.369G>T	p.Thr123Thr	synonymous	Exon 5 of 15	ENSP00000623410.1

Frequencies

GnomAD3 genomes AF: 0.992 AC: 107470 AN: 108293 Hom.: 38262 Cov.: 20

Gnomad AFR AF: 0.974

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.996

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.996

GnomAD2 exomes AF: 0.998 AC: 183046 AN: 183423 AF XY: 0.999

Gnomad AFR exome AF: 0.976

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.999 AC: 1097289 AN: 1098163 Hom.: 366695 Cov.: 47 AF XY: 0.999 AC XY: 363283 AN XY: 363517

African (AFR) AF: 0.975 AC: 25742 AN: 26402

American (AMR) AF: 0.998 AC: 35129 AN: 35206

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 19385 AN: 19385

East Asian (EAS) AF: 1.00 AC: 30205 AN: 30205

South Asian (SAS) AF: 1.00 AC: 54137 AN: 54146

European-Finnish (FIN) AF: 1.00 AC: 40533 AN: 40533

Middle Eastern (MID) AF: 1.00 AC: 4128 AN: 4130

European-Non Finnish (NFE) AF: 1.00 AC: 842044 AN: 842061

Other (OTH) AF: 0.998 AC: 45986 AN: 46095

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.992 AC: 107516 AN: 108344 Hom.: 38257 Cov.: 20 AF XY: 0.993 AC XY: 30401 AN XY: 30606

African (AFR) AF: 0.974 AC: 28880 AN: 29655

American (AMR) AF: 0.996 AC: 10085 AN: 10129

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2611 AN: 2611

East Asian (EAS) AF: 1.00 AC: 3458 AN: 3458

South Asian (SAS) AF: 1.00 AC: 2445 AN: 2445

European-Finnish (FIN) AF: 1.00 AC: 5397 AN: 5397

Middle Eastern (MID) AF: 0.995 AC: 212 AN: 213

European-Non Finnish (NFE) AF: 1.00 AC: 52285 AN: 52287

Other (OTH) AF: 0.996 AC: 1466 AN: 1472

Alfa AF: 0.998 Hom.: 17057

Bravo AF: 0.991

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Dyskeratosis congenita, X-linked (2)
-	-	2	not provided (2)
-	-	1	Dyskeratosis congenita (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.7
DANN	Benign	0.88
PhyloP100		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs2728532; hg19: chrX-153994596; COSMIC: COSV108201298; COSMIC: COSV108201298;