X-154762824-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000620277.4(DKC1):n.83C>G 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 0.0035 in 790,181 control chromosomes in the GnomAD database, including 1 homozygotes. There are 715 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., 67 hem., cov: 25)
  • Exomes 𝑓: 0.0037 (1 hom. 648 hem.)
• Consequence: DKC1 ENST00000620277.4 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4 B:7 O:1
• Conservation: PhyloP100: 0.868

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00371 (2510/676450) while in subpopulation NFE AF= 0.00486 (2381/490002). AF 95% confidence interval is 0.0047. There are 1 homozygotes in gnomad4_exome. There are 648 alleles in male gnomad4_exome subpopulation. Median coverage is 10. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd at 67 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DKC1	NM_001363.5			upstream_gene_variant		ENST00000369550.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DKC1	ENST00000369550.10			upstream_gene_variant		1	NM_001363.5	P2

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 254 AN: 113679 Hom.: 0 Cov.: 25 AF XY: 0.00187 AC XY: 67 AN XY: 35819

Gnomad AFR AF: 0.000638

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000915

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: 0.00434

Gnomad OTH AF: 0.000648

GnomAD4 exome AF: 0.00371 AC: 2510 AN: 676450 Hom.: 1 Cov.: 10 AF XY: 0.00359 AC XY: 648 AN XY: 180692

Gnomad4 AFR exome AF: 0.000604

Gnomad4 AMR exome AF: 0.000446

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000254

Gnomad4 FIN exome AF: 0.000398

Gnomad4 NFE exome AF: 0.00486

Gnomad4 OTH exome AF: 0.00265

GnomAD4 genome AF: 0.00223 AC: 254 AN: 113731 Hom.: 0 Cov.: 25 AF XY: 0.00187 AC XY: 67 AN XY: 35881

Gnomad4 AFR AF: 0.000636

Gnomad4 AMR AF: 0.0000914

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00434

Gnomad4 OTH AF: 0.000639

Alfa AF: 0.00108 Hom.: 8

Bravo AF: 0.00208

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dyskeratosis congenita, X-linked Pathogenic:2 Uncertain:1 Benign:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Dec 08, 2023	- This variant has been reported in individuals with dyskeratosis congenita (PMID: 11379875, 32426895), aplastic anemia (PMID: 27418648), immunodeficiency (PMID: 32166868) and in patients with osteosarcoma (PMID: 32191290). – not specific enough. - This variant has been observed in gnomADv4 with a frequency of 0.35% (715 hemizygotes, 1 homozygote). – meeting BA1. - Functional studies suggest that this variant results in shortened telomere length by flow cytometry (PMID: 32166868). This variant is found in the untranslated region (5' UTR). This promoter region (c.-143 to -c.134) contains a canonical transcription binding site of the DKC1 gene (PMID: 10592259). In vitro transcriptional activation studies show that this variant reduces the promoter activity (PMID 12137939). – PS3 but not strong enough. We now agree that this variant should be called likely benign mainly due to the most recent gnomAD v4 frequency being too high to cause disease. The criteria met is BA1, PS3_supporting. -
Likely benign, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies	-	Variant interpreted as Pathogenic and reported on 01-05-2017 by GTR ID 1006. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect facilitates ClinVar submission from the Association for Creatine Deficiencies registry and does not attempt to reinterpret the variant. -
Pathogenic, flagged submission	curation	GeneReviews	May 10, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 01, 2019	The DKC1 c.-142C>G variant occurs in the 5’ untranslated region and has been reported in two studies in which it was identified in three total hemizygotes and one heterozygous carrier (Knight et al. 2001; Keel et al. 2016). Knight et al. (2001) identified a pair of hemizygous brothers with dyskeratosis congenita who inherited the variant from their unaffected mother. A hemizygote with aplastic anemia was found by Keel et al. (2016). The variant was absent from 100 control X-chromosomes. The c.-142C>G is reported at a frequency of 0.004066 in the European (non-Finnish) population of the Genome Aggregation Database and is found in 18 hemizygotes. This allele frequency is high but may be consistent with reduced penetrance. The variant disrupts a canonical Sp1 transcription factor binding site (Knight et al. 2001) and was found to reduce promoter activity by 60% compared to Wild Type by Salowsky et al. (2002). Based on the conflicting evidence from the literature and the frequency databases, the c.-142C>G variant is classified as a variant of uncertain significance for dyskeratosis congenita. -
Pathogenic, flagged submission	literature only	OMIM	Jun 26, 2002	- -

Dyskeratosis congenita Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 24, 2018	The c.-142C>G variant (also known as c.-141C>G) is located in the 5' untranslated region (5’ UTR) of the DKC1 gene. This variant results from a C to G substitution 142 bases upstream from the first translated codon. This variant has been reported in two male siblings with dyskeratosis congenita and a male with aplastic anemia (Knight SW et al. Hum. Genet., 2001 Apr;108:299-303; Keel SB et al. Haematologica, 2016 11;101:1343-1350). This variant was also identified in another individual with severe clinical features of dyskeratosis congenita, whose hematopoietic progenitor cells had reduced DKC1 expression (Bellodi C et al. Cell Rep, 2013 May;3:1493-502). An in vitro functional study found that this variant reduced promoter activity to 60% of wild type (Salowsky R et al. Gene, 2002 Jun;293:9-19). However, this variant did not co-segregate with disease in multiple males tested in our laboratory. In addition, based on data from gnomAD, the G allele has an overall frequency of approximately 0.2% (46/21778) total alleles studied, and it was detected in 16 hemizygous individuals. This nucleotide position is not well conserved in available vertebrate species on limited alignment. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	DKC1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2021	Reported in published literature in association with dyskeratosis congenita and aplastic anemia (Knight et al., 2001; Keel et al., 2016); Nucleotide substitution has no predicted effect on splicing and is not conserved across species; This variant is associated with the following publications: (PMID: 32426895, 32191290, 11379875, 14556776, 27418648, 12137939, 11054058, 20301779, 25326635, 32166868) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 03, 2016	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 25, 2017

- -

DKC1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 27, 2023

The DKC1 c.-142C>G variant is located in the 5' untranslated region. This variant was reported in the hemizygous state in two brothers with dyskeratosis congenita and in the heterozygous state in their mother (referred to as c.-141C>G, Knight et al. 2001. PubMed ID: 11379875). It was also reported in a patient with aplastic anemia (Keel et al. 2016. PubMed ID: 27418648). This variant is located in a canonical transcription factor binding site and may alter proper transcription factor binding (Salowsky et al. 2002. PubMed ID: 12137939). This variant is also found in non-Finnish Europeans at a frequency of 0.4% and is found in many individuals in the hemizygous state. Given the high allele frequency of this variant, we suspect it is not a primary cause of disease, however, due to the absence of conclusive functional and genetic evidence, its significance remains uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	7.7
Dann	Benign	0.66

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

LitVar

Other links and lift over

dbSNP: rs199422241; hg19: chrX-153991099;