chr3-134209737-A-G

Variant names:

• chr3-134209737-A-G
• NM_002958.4:c.547T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002958.4(RYK):​c.547T>C​(p.Phe183Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RYK NM_002958.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20756367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYK	NM_002958.4	c.547T>C	p.Phe183Leu	missense_variant	Exon 4 of 15	ENST00000623711.4	NP_002949.2
RYK	NM_001005861.3	c.547T>C	p.Phe183Leu	missense_variant	Exon 4 of 15		NP_001005861.1
RYK	XR_007095716.1	n.752T>C		non_coding_transcript_exon_variant	Exon 4 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYK	ENST00000623711.4	c.547T>C	p.Phe183Leu	missense_variant	Exon 4 of 15	1	NM_002958.4	ENSP00000485095.1
RYK	ENST00000620660.4	c.547T>C	p.Phe183Leu	missense_variant	Exon 4 of 15	1		ENSP00000478721.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.547T>C (p.F183L) alteration is located in exon 4 (coding exon 4) of the RYK gene. This alteration results from a T to C substitution at nucleotide position 547, causing the phenylalanine (F) at amino acid position 183 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	-0.073
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;T;T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.77	T
Sift4G	Benign	0.65	T;T;T
Vest4		0.45, 0.45
MVP		0.49
ClinPred		0.75	D
GERP RS		5.9
Varity_R		0.10
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-133928581;