rs10935104

Positions:

• chr3-134164217-T-A

Variant summary

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

The NM_002958.4(RYK):​c.1576-4844A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 152,122 control chromosomes in the GnomAD database, including 5,992 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 0.24 (5992 hom., cov: 32)
• Consequence: RYK NM_002958.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.671

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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYK	NM_002958.4	c.1576-4844A>T		intron_variant		ENST00000623711.4
RYK	NM_001005861.3	c.1585-4844A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYK	ENST00000623711.4	c.1576-4844A>T		intron_variant		1	NM_002958.4	A2

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36260 AN: 152004 Hom.: 5972 Cov.: 32

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.785

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.231

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

GnomAD4 genome AF: 0.239 AC: 36310 AN: 152122 Hom.: 5992 Cov.: 32 AF XY: 0.250 AC XY: 18587 AN XY: 74354

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.358

Gnomad4 ASJ AF: 0.134

Gnomad4 EAS AF: 0.786

Gnomad4 SAS AF: 0.484

Gnomad4 FIN AF: 0.173

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.237

Alfa AF: 0.175 Hom.: 416

Bravo AF: 0.254

Asia WGS AF: 0.660 AC: 2292 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.71
DANN	Benign	0.63

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: rs10935104; hg19: chr3-133883061;