rs200780796

Positions:

chr1-205211450-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_015375.3(DSTYK):c.86G>A(p.Arg29Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000658 in 1,599,294 control chromosomes in the GnomAD database, including 2 homozygotes. 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 0.00072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00065 ( 2 hom. )

Consequence

DSTYK
NM_015375.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.21

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012831062).

BP6

Variant 1-205211450-C-T is Benign according to our data. Variant chr1-205211450-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 60687.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 110 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSTYK	NM_015375.3 linkuse as main transcript	c.86G>A	p.Arg29Gln	missense_variant	1/13	ENST00000367162.8	NP_056190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSTYK	ENST00000367162.8 linkuse as main transcript	c.86G>A	p.Arg29Gln	missense_variant	1/13	1	NM_015375.3	ENSP00000356130	P1	Q6XUX3-1
DSTYK	ENST00000367161.7 linkuse as main transcript	c.86G>A	p.Arg29Gln	missense_variant	1/12	1		ENSP00000356129		Q6XUX3-2

Frequencies

GnomAD3 genomes

AF:

0.000723

AC:

110

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00101

AC:

223

AN:

220688

Hom.:

AF XY:

0.00123

AC XY:

149

AN XY:

121330

show subpopulations

Gnomad AFR exome

AF:

0.0000745

Gnomad AMR exome

AF:

0.000545

Gnomad ASJ exome

AF:

0.00786

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00186

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000738

Gnomad OTH exome

AF:

0.000547

GnomAD4 exome

AF:

0.000651

AC:

942

AN:

1446952

Hom.:

Cov.:

AF XY:

0.000732

AC XY:

527

AN XY:

719528

show subpopulations

Gnomad4 AFR exome

AF:

0.000121

Gnomad4 AMR exome

AF:

0.000797

Gnomad4 ASJ exome

AF:

0.00894

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00169

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000417

Gnomad4 OTH exome

AF:

0.000935

GnomAD4 genome

AF:

0.000722

AC:

110

AN:

152342

Hom.:

Cov.:

AF XY:

0.000805

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.00922

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00125

Hom.:

Bravo

AF:

0.000907

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000669

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The DSTYK p.Arg29Gln variant was identified in 3 of 622 proband chromosomes (frequency: 0.0048) from individuals with congenital abnormalities of the kidney and urinary tract and was not identified in 768 control chromosomes from healthy individuals (Sanna-Cherchi_2013_PMID:23862974). The variant was identified in dbSNP (ID: rs200780796) and ClinVar (classified as likely benign by Invitae and benign by Mendelics). The variant was identified in control databases in 228 of 252060 chromosomes at a frequency of 0.0009045 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 75 of 9706 chromosomes (freq: 0.007727), South Asian in 54 of 28984 chromosomes (freq: 0.001863), European (non-Finnish) in 75 of 114366 chromosomes (freq: 0.000656), Other in 4 of 6568 chromosomes (freq: 0.000609), Latino in 19 of 33852 chromosomes (freq: 0.000561) and African in 1 of 22128 chromosomes (freq: 0.000045), but was not observed in the East Asian or European (Finnish) populations. The p.Arg29 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -

Congenital anomalies of kidney and urinary tract 1

Pathogenic:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 15, 2013	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 22, 2023	Variant summary: RIPK5 (also known as DSTYK) c.86G>A (p.Arg29Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0009 in 252060 control chromosomes (gnomAD), predominantly at a frequency of 0.0019 within the South Asian subpopulation in the gnomAD database. c.86G>A has been reported in the literature in individuals affected with congenital abnormalities of the kidney and urinary tract (Sanna-Cherchi_2013). This report does not provide unequivocal conclusions about association of the variant with RIPK5-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.012

.;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.88

D;D

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.013

T;T

MetaSVM

Uncertain

0.13

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.75

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.45

T;T

Sift4G

Benign

0.36

T;T

Polyphen

1.0

D;D

Vest4

0.56

MutPred

0.41

Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);

MVP

0.83

MPC

0.62

ClinPred

0.21

GERP RS

5.2

Varity_R

0.45

gMVP

0.51

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

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