rs201091809

Positions:

chr1-205187417-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PVS1_StrongPP5BS2

The NM_015375.3(DSTYK):c.654+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000367 in 1,602,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

DSTYK
NM_015375.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 7.52

Variant links:

Genes affected

DSTYK (HGNC:29043): (dual serine/threonine and tyrosine protein kinase) This gene encodes a dual serine/threonine and tyrosine protein kinase which is expressed in multiple tissues. It is thought to function as a regulator of cell death. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

DSTYK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.1390681 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.6, offset of -27, new splice context is: gagGTaacg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PP5

Variant 1-205187417-C-T is Pathogenic according to our data. Variant chr1-205187417-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 60684.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

BS2

High AC in GnomAd4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSTYK	NM_015375.3 linkuse as main transcript	c.654+1G>A		splice_donor_variant, intron_variant		ENST00000367162.8	NP_056190.1	Q6XUX3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSTYK	ENST00000367162.8 linkuse as main transcript	c.654+1G>A		splice_donor_variant, intron_variant		1	NM_015375.3	ENSP00000356130.3		Q6XUX3-1
DSTYK	ENST00000367161.7 linkuse as main transcript	c.654+1G>A		splice_donor_variant, intron_variant		1		ENSP00000356129.3		Q6XUX3-2

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.000368

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000278

AC:

AN:

244538

Hom.:

AF XY:

0.000303

AC XY:

AN XY:

131984

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000828

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000334

Gnomad OTH exome

AF:

0.000337

GnomAD4 exome

AF:

0.000376

AC:

545

AN:

1450288

Hom.:

Cov.:

AF XY:

0.000397

AC XY:

286

AN XY:

719784

show subpopulations

Gnomad4 AFR exome

AF:

0.0000902

Gnomad4 AMR exome

AF:

0.000774

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000442

Gnomad4 OTH exome

AF:

0.000301

GnomAD4 genome

AF:

0.000282

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000357

Hom.:

Bravo

AF:

0.000276

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000239

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 23

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)

Apr 27, 2023

- -

Congenital anomalies of kidney and urinary tract 1

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Aug 15, 2013

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 04, 2022

This sequence change affects a donor splice site in intron 2 of the DSTYK gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 9 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs201091809, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with congenital abnormalities of the kidney and urinary tract (PMID: 23862974). ClinVar contains an entry for this variant (Variation ID: 60684). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 2 (PMID: 23862974). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

DSTYK-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 23, 2024

The DSTYK c.654+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in at least seven individuals from a single family with renal hypodysplasia, ureteropelvic junction obstruction and vesicoureteral reflux, as well as two unaffected family members and several family members with unknown phenotype (Sanna-Cherchi et al 2013. PubMed ID: 23862974). This variant has also been reported in the heterozygous state in a patient with branchiootorenal syndrome features but normal renal ultrasound, and incomplete penetrance was suggested (Heidet et al 2017. PubMed ID: 28566479). This variant is reported in 0.081% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.98

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.96

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.96

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over