3-134191891-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_002958.4(RYK):c.973A>C(p.Ile325Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYK NM_002958.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.16

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=0.28166774).
• BP6: Variant 3-134191891-T-G is Benign according to our data. Variant chr3-134191891-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2363166.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYK	NM_002958.4	c.973A>C	p.Ile325Leu	missense_variant	8/15	ENST00000623711.4
RYK	NM_001005861.3	c.982A>C	p.Ile328Leu	missense_variant	8/15
RYK	XR_007095716.1	n.1187A>C		non_coding_transcript_exon_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYK	ENST00000623711.4	c.973A>C	p.Ile325Leu	missense_variant	8/15	1	NM_002958.4	A2
RYK	ENST00000620660.4	c.982A>C	p.Ile328Leu	missense_variant	8/15	1		P4
RYK	ENST00000480381.1	n.342A>C		non_coding_transcript_exon_variant	2/4	5
RYK	ENST00000486725.1	c.28A>C	p.Ile10Leu	missense_variant, NMD_transcript_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2022

The c.982A>C (p.I328L) alteration is located in exon 8 (coding exon 8) of the RYK gene. This alteration results from a A to C substitution at nucleotide position 982, causing the isoleucine (I) at amino acid position 328 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

RYK-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.21	T;.;.
Eigen	Benign	-0.024
Eigen_PC	Benign	0.093
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D;T;D
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
Sift4G	Uncertain	0.020	D;T;T
Vest4		0.50, 0.49
MVP		0.44
ClinPred		0.68	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.61
gMVP		0.48

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: chr3-133910735;