3-134212160-T-C

Position:

• chr3-134212160-T-C

Variant summary

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

The NM_002958.4(RYK):​c.355-553A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 148,884 control chromosomes in the GnomAD database, including 8,608 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 0.31 (8608 hom., cov: 32)
• Consequence: RYK NM_002958.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.234

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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYK	NM_002958.4	c.355-553A>G		intron_variant		ENST00000623711.4
RYK	NM_001005861.3	c.355-553A>G		intron_variant
RYK	XR_007095716.1	n.560-553A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYK	ENST00000623711.4	c.355-553A>G		intron_variant		1	NM_002958.4	A2
RYK	ENST00000620660.4	c.355-553A>G		intron_variant		1		P4

Frequencies

GnomAD3 genomes AF: 0.314 AC: 46683 AN: 148772 Hom.: 8602 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.477

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.353

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

GnomAD4 genome AF: 0.313 AC: 46673 AN: 148884 Hom.: 8608 Cov.: 32 AF XY: 0.317 AC XY: 22965 AN XY: 72524

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.550

Gnomad4 EAS AF: 0.226

Gnomad4 SAS AF: 0.365

Gnomad4 FIN AF: 0.468

Gnomad4 NFE AF: 0.401

Gnomad4 OTH AF: 0.351

Alfa AF: 0.353 Hom.: 4900

Bravo AF: 0.285

Asia WGS AF: 0.220 AC: 762 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	5.7
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs9859680; hg19: chr3-133931004;