rs9283588

Positions:

• chr3-134155722-A-G
• chr3-134155722-A-T

Variant summary

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

The ENST00000484106.3(RYK):​c.435+19887T>C variant causes a intron, NMD transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 152,164 control chromosomes in the GnomAD database, including 2,554 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2554 hom., cov: 32)
• Consequence: RYK ENST00000484106.3 intron, NMD_transcript
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58

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 (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYK	ENST00000484106.3	c.435+19887T>C		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25391 AN: 152046 Hom.: 2538 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.0839

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.160

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.167 AC: 25433 AN: 152164 Hom.: 2554 Cov.: 32 AF XY: 0.169 AC XY: 12574 AN XY: 74382

Gnomad4 AFR AF: 0.215

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.0839

Gnomad4 EAS AF: 0.475

Gnomad4 SAS AF: 0.161

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.117

Gnomad4 OTH AF: 0.164

Alfa AF: 0.0868 Hom.: 751

Bravo AF: 0.173

Asia WGS AF: 0.336 AC: 1167 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	12
DANN	Benign	0.84

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs9283588; hg19: chr3-133874566;