rs4470517

Positions:

• chr3-134163307-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_002958.4(RYK):​c.1576-3934C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.737 in 152,092 control chromosomes in the GnomAD database, including 41,874 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 0.74 (41874 hom., cov: 32)
• Consequence: RYK NM_002958.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.912

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYK	NM_002958.4	c.1576-3934C>T		intron_variant		ENST00000623711.4	NP_002949.2
RYK	NM_001005861.3	c.1585-3934C>T		intron_variant			NP_001005861.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYK	ENST00000623711.4	c.1576-3934C>T		intron_variant		1	NM_002958.4	ENSP00000485095.1

Frequencies

GnomAD3 genomes AF: 0.737 AC: 111998 AN: 151974 Hom.: 41849 Cov.: 32

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.772

Gnomad ASJ AF: 0.791

Gnomad EAS AF: 0.992

Gnomad SAS AF: 0.933

Gnomad FIN AF: 0.713

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.670

Gnomad OTH AF: 0.757

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

GnomAD4 genome AF: 0.737 AC: 112077 AN: 152092 Hom.: 41874 Cov.: 32 AF XY: 0.745 AC XY: 55351 AN XY: 74338

Gnomad4 AFR AF: 0.782

Gnomad4 AMR AF: 0.773

Gnomad4 ASJ AF: 0.791

Gnomad4 EAS AF: 0.992

Gnomad4 SAS AF: 0.934

Gnomad4 FIN AF: 0.713

Gnomad4 NFE AF: 0.670

Gnomad4 OTH AF: 0.758

Alfa AF: 0.699 Hom.: 63956

Bravo AF: 0.741

Asia WGS AF: 0.941 AC: 3270 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Benign	0.86

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: rs4470517; hg19: chr3-133882151;