1-205147572-C-T

Variant names:

• chr1-205147572-C-T
• rs148542303
• NM_015375.3:c.2776G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015375.3(DSTYK):​c.2776G>A​(p.Asp926Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D926Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DSTYK NM_015375.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.08
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• congenital anomalies of kidney and urinary tract 1

  Inheritance: AD, AR Classification: DEFINITIVE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary spastic paraplegia 23

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P
• complex hereditary spastic paraplegia

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31285775).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015375.3. 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
	DSTYK	NM_015375.3	MANE Select	c.2776G>A	p.Asp926Asn	missense	Exon 13 of 13	NP_056190.1	Q6XUX3-1
	DSTYK	NM_199462.3		c.2641G>A	p.Asp881Asn	missense	Exon 12 of 12	NP_955749.1	Q6XUX3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSTYK	ENST00000367162.8	TSL:1 MANE Select	c.2776G>A	p.Asp926Asn	missense	Exon 13 of 13	ENSP00000356130.3	Q6XUX3-1
	DSTYK	ENST00000367161.7	TSL:1	c.2641G>A	p.Asp881Asn	missense	Exon 12 of 12	ENSP00000356129.3	Q6XUX3-2
	DSTYK	ENST00000893236.1		c.2749G>A	p.Asp917Asn	missense	Exon 13 of 13	ENSP00000563295.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250638 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457784 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724276

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.0000672 AC: 3 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108568

Other (OTH) AF: 0.00 AC: 0 AN: 60178

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0067	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.9	M
PhyloP100		7.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.031	D
Polyphen		0.90	P
Vest4		0.33
MutPred		0.15		Loss of phosphorylation at T929 (P = 0.0743)
MVP		0.75
MPC		0.58
ClinPred		0.79	D
GERP RS		6.1
Varity_R		0.091
gMVP		0.43
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs148542303; hg19: chr1-205116700;