3-134149953-T-C

Variant names:

• chr3-134149953-T-C
• rs4072181
• ENST00000484106.3:n.435+25656A>G

Variant summary

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

The ENST00000484106.3(RYK):​n.435+25656A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.045 in 152,358 control chromosomes in the GnomAD database, including 186 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 0.045 (186 hom., cov: 32)
• Consequence: RYK ENST00000484106.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.215

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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYK	ENST00000484106.3	n.435+25656A>G		intron_variant	Intron 4 of 6	5		ENSP00000487023.1

Frequencies

GnomAD3 genomes AF: 0.0449 AC: 6841 AN: 152240 Hom.: 185 Cov.: 32

Gnomad AFR AF: 0.0317

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0559

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.0463

Gnomad FIN AF: 0.0431

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0447

Gnomad OTH AF: 0.0587

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

GnomAD4 genome AF: 0.0450 AC: 6850 AN: 152358 Hom.: 186 Cov.: 32 AF XY: 0.0445 AC XY: 3318 AN XY: 74504

Gnomad4 AFR AF: 0.0317

Gnomad4 AMR AF: 0.0561

Gnomad4 ASJ AF: 0.0288

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.0468

Gnomad4 FIN AF: 0.0431

Gnomad4 NFE AF: 0.0447

Gnomad4 OTH AF: 0.0581

Alfa AF: 0.0486 Hom.: 238

Bravo AF: 0.0480

Asia WGS AF: 0.0830 AC: 289 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.7
DANN	Benign	0.67

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4072181; hg19: chr3-133868797;