Variant chr3-134222476-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002958.4(RYK):c.296G>A(p.Ser99Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,612,718 control chromosomes in the GnomAD database, including 19,252 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.15 ( 2079 hom., cov: 32)

Exomes 𝑓: 0.14 ( 17173 hom. )

Consequence

RYK
NM_002958.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.29

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013491809).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYK	NM_002958.4 link	c.296G>A	p.Ser99Asn	missense_variant	2/15	ENST00000623711.4	NP_002949.2	P34925-1Q59FQ5Q8WTZ8
RYK	NM_001005861.3 link	c.296G>A	p.Ser99Asn	missense_variant	2/15		NP_001005861.1	P34925-2Q59FQ5Q8WTZ8
RYK	XR_007095716.1 link	n.501G>A		non_coding_transcript_exon_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYK	ENST00000623711.4 link	c.296G>A	p.Ser99Asn	missense_variant	2/15	1	NM_002958.4	ENSP00000485095.1		P34925-1
RYK	ENST00000620660.4 link	c.296G>A	p.Ser99Asn	missense_variant	2/15	1		ENSP00000478721.1		P34925-2

Frequencies

GnomAD3 genomes

AF:

0.150

AC:

22820

AN:

151770

Hom.:

2065

Cov.:

show subpopulations

Gnomad AFR

AF:

0.154

Gnomad AMI

AF:

0.0998

Gnomad AMR

AF:

0.193

Gnomad ASJ

AF:

0.0842

Gnomad EAS

AF:

0.472

Gnomad SAS

AF:

0.159

Gnomad FIN

AF:

0.149

Gnomad MID

AF:

0.144

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.149

GnomAD3 exomes

AF:

0.163

AC:

40560

AN:

248884

Hom.:

4400

AF XY:

0.159

AC XY:

21422

AN XY:

135036

show subpopulations

Gnomad AFR exome

AF:

0.149

Gnomad AMR exome

AF:

0.214

Gnomad ASJ exome

AF:

0.0863

Gnomad EAS exome

AF:

0.459

Gnomad SAS exome

AF:

0.148

Gnomad FIN exome

AF:

0.144

Gnomad NFE exome

AF:

0.117

Gnomad OTH exome

AF:

0.149

GnomAD4 exome

AF:

0.137

AC:

200337

AN:

1460828

Hom.:

17173

Cov.:

AF XY:

0.137

AC XY:

99543

AN XY:

726728

show subpopulations

Gnomad4 AFR exome

AF:

0.148

Gnomad4 AMR exome

AF:

0.214

Gnomad4 ASJ exome

AF:

0.0906

Gnomad4 EAS exome

AF:

0.501

Gnomad4 SAS exome

AF:

0.151

Gnomad4 FIN exome

AF:

0.141

Gnomad4 NFE exome

AF:

0.120

Gnomad4 OTH exome

AF:

0.148

GnomAD4 genome

AF:

0.150

AC:

22857

AN:

151890

Hom.:

2079

Cov.:

AF XY:

0.153

AC XY:

11370

AN XY:

74222

show subpopulations

Gnomad4 AFR

AF:

0.154

Gnomad4 AMR

AF:

0.194

Gnomad4 ASJ

AF:

0.0842

Gnomad4 EAS

AF:

0.472

Gnomad4 SAS

AF:

0.159

Gnomad4 FIN

AF:

0.149

Gnomad4 NFE

AF:

0.118

Gnomad4 OTH

AF:

0.153

Alfa

AF:

0.126

Hom.:

747

Bravo

AF:

0.155

TwinsUK

AF:

0.123

AC:

457

ALSPAC

AF:

0.120

AC:

464

ESP6500AA

AF:

0.150

AC:

566

ESP6500EA

AF:

0.117

AC:

962

ExAC

AF:

0.160

AC:

19275

Asia WGS

AF:

0.331

AC:

1149

AN:

3478

EpiCase

AF:

0.119

EpiControl

AF:

0.116

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;.;.

Eigen

Benign

0.021

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.17

T;T;T

MetaRNN

Benign

0.0013

T;T;T

MetaSVM

Benign

-0.88

PrimateAI

Uncertain

0.66

PROVEAN

Benign

0.080

N;.;.

Sift

Benign

0.073

T;.;.

Sift4G

Benign

0.41

T;T;T

Vest4

0.042, 0.032

ClinPred

0.010

GERP RS

6.0

Varity_R

0.036

gMVP

0.10

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over