rs4339087

Positions:

• chr3-134230869-C-T

Variant summary

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

The NM_002958.4(RYK):​c.233-8330G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 152,112 control chromosomes in the GnomAD database, including 1,011 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 0.11 (1011 hom., cov: 32)
• Consequence: RYK NM_002958.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.666

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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYK	NM_002958.4	c.233-8330G>A		intron_variant		ENST00000623711.4	NP_002949.2
RYK	NM_001005861.3	c.233-8330G>A		intron_variant			NP_001005861.1
RYK	XR_007095716.1	n.438-8330G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYK	ENST00000623711.4	c.233-8330G>A		intron_variant		1	NM_002958.4	ENSP00000485095	A2
RYK	ENST00000620660.4	c.233-8330G>A		intron_variant		1		ENSP00000478721	P4

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17023 AN: 151994 Hom.: 1011 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.0709

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.115

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

GnomAD4 genome AF: 0.112 AC: 17018 AN: 152112 Hom.: 1011 Cov.: 32 AF XY: 0.109 AC XY: 8119 AN XY: 74360

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.121

Gnomad4 FIN AF: 0.0709

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.114

Alfa AF: 0.128 Hom.: 1165

Bravo AF: 0.112

Asia WGS AF: 0.0430 AC: 150 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.0
DANN	Benign	0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs4339087; hg19: chr3-133949713;