Variant chr3-134250508-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_002958.4(RYK):c.147C>T(p.Ala49=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,246,878 control chromosomes in the GnomAD database, including 14,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.14 ( 1924 hom., cov: 30)

Exomes 𝑓: 0.13 ( 12161 hom. )

Consequence

RYK
NM_002958.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.831

Variant links:

Genes affected

RYK (HGNC:10481): (receptor like tyrosine kinase) The protein encoded by this gene is an atypical member of the family of growth factor receptor protein tyrosine kinases, differing from other members at a number of conserved residues in the activation and nucleotide binding domains. This gene product belongs to a subfamily whose members do not appear to be regulated by phosphorylation in the activation segment. It has been suggested that mediation of biological activity by recruitment of a signaling-competent auxiliary protein may occur through an as yet uncharacterized mechanism. The encoded protein has a leucine-rich extracellular domain with a WIF-type Wnt binding region, a single transmembrane domain, and an intracellular tyrosine kinase domain. This protein is involved in stimulating Wnt signaling pathways such as the regulation of axon pathfinding. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2012]

RYK links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 3-134250508-G-A is Benign according to our data. Variant chr3-134250508-G-A is described in ClinVar as [Benign]. Clinvar id is 3048012.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.831 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RYK	NM_002958.4 linkuse as main transcript	c.147C>T	p.Ala49=	synonymous_variant	1/15	ENST00000623711.4	NP_002949.2
RYK	NM_001005861.3 linkuse as main transcript	c.147C>T	p.Ala49=	synonymous_variant	1/15		NP_001005861.1
RYK	XR_007095716.1 linkuse as main transcript	n.352C>T		non_coding_transcript_exon_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYK	ENST00000623711.4 linkuse as main transcript	c.147C>T	p.Ala49=	synonymous_variant	1/15	1	NM_002958.4	ENSP00000485095	A2	P34925-1
RYK	ENST00000620660.4 linkuse as main transcript	c.147C>T	p.Ala49=	synonymous_variant	1/15	1		ENSP00000478721	P4	P34925-2

Frequencies

GnomAD3 genomes

AF:

0.143

AC:

21692

AN:

151204

Hom.:

1911

Cov.:

show subpopulations

Gnomad AFR

AF:

0.132

Gnomad AMI

AF:

0.100

Gnomad AMR

AF:

0.185

Gnomad ASJ

AF:

0.0860

Gnomad EAS

AF:

0.475

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.147

Gnomad MID

AF:

0.143

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.143

GnomAD3 exomes

AF:

0.191

AC:

2838

AN:

14856

Hom.:

257

AF XY:

0.191

AC XY:

1820

AN XY:

9526

show subpopulations

Gnomad AFR exome

AF:

0.195

Gnomad AMR exome

AF:

0.260

Gnomad ASJ exome

AF:

0.138

Gnomad EAS exome

AF:

0.541

Gnomad SAS exome

AF:

0.200

Gnomad FIN exome

AF:

0.210

Gnomad NFE exome

AF:

0.167

Gnomad OTH exome

AF:

0.193

GnomAD4 exome

AF:

0.134

AC:

146474

AN:

1095566

Hom.:

12161

Cov.:

AF XY:

0.134

AC XY:

70341

AN XY:

526194

show subpopulations

Gnomad4 AFR exome

AF:

0.132

Gnomad4 AMR exome

AF:

0.213

Gnomad4 ASJ exome

AF:

0.0968

Gnomad4 EAS exome

AF:

0.520

Gnomad4 SAS exome

AF:

0.163

Gnomad4 FIN exome

AF:

0.143

Gnomad4 NFE exome

AF:

0.121

Gnomad4 OTH exome

AF:

0.151

GnomAD4 genome

AF:

0.144

AC:

21719

AN:

151312

Hom.:

1924

Cov.:

AF XY:

0.147

AC XY:

10835

AN XY:

73942

show subpopulations

Gnomad4 AFR

AF:

0.132

Gnomad4 AMR

AF:

0.186

Gnomad4 ASJ

AF:

0.0860

Gnomad4 EAS

AF:

0.476

Gnomad4 SAS

AF:

0.162

Gnomad4 FIN

AF:

0.147

Gnomad4 NFE

AF:

0.118

Gnomad4 OTH

AF:

0.147

Alfa

AF:

0.0490

Hom.:

Bravo

AF:

0.147

Asia WGS

AF:

0.322

AC:

1078

AN:

3358

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

RYK-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

DANN

Benign

0.94

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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