3-134222476-C-T

Position:

• chr3-134222476-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000623711.4(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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (2079 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17173 hom.)
• Consequence: RYK ENST00000623711.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.29

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]

ACMG classification

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	c.296G>A	p.Ser99Asn	missense_variant	2/15	ENST00000623711.4	NP_002949.2
RYK	NM_001005861.3	c.296G>A	p.Ser99Asn	missense_variant	2/15		NP_001005861.1
RYK	XR_007095716.1	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	c.296G>A	p.Ser99Asn	missense_variant	2/15	1	NM_002958.4	ENSP00000485095	A2
RYK	ENST00000620660.4	c.296G>A	p.Ser99Asn	missense_variant	2/15	1		ENSP00000478721	P4

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22820 AN: 151770 Hom.: 2065 Cov.: 32

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

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.: 31 AF XY: 0.137 AC XY: 99543 AN XY: 726728

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.: 32 AF XY: 0.153 AC XY: 11370 AN XY: 74222

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	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	0.021
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.17	T;T;T
MetaRNN	Benign	0.0013	T;T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	4.2e-12	P
PrimateAI	Uncertain	0.66	T
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	T
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

Other links and lift over

dbSNP: rs1131262; hg19: chr3-133941320; COSMIC: COSV56061360;