rs201091809

chr1-205187417-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1_Strong PP3_Strong PP5 BS2

The NM_015375.3(DSTYK):c.654+1G>A variant causes a splice donor 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. 2/2 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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 7.52

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Splicing variant, 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.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• 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: {Pathogenic=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSTYK	NM_015375.3	c.654+1G>A		splice_donor_variant		ENST00000367162.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSTYK	ENST00000367162.8	c.654+1G>A		splice_donor_variant		1	NM_015375.3	P1
DSTYK	ENST00000367161.7	c.654+1G>A		splice_donor_variant		1

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152116 Hom.: 0 Cov.: 32

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: 68 AN: 244538 Hom.: 0 AF XY: 0.000303 AC XY: 40 AN XY: 131984

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.: 0 Cov.: 31 AF XY: 0.000397 AC XY: 286 AN XY: 719784

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: 43 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74430

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.: 0

Bravo AF: 0.000276

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000239 AC: 29

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

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

Invitae

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 condition Uncertain:1

Uncertain significance, criteria provided, single submitter

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	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D
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

Other links and lift over

dbSNP: rs201091809; hg19: chr1-205156545;