NM_002958.4:c.973A>C

Variant names:

• chr3-134191891-T-G
• rs1425051712
• NM_002958.4:c.973A>C

Variant summary

Our verdict is Uncertain significance. The variant received 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. 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 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 VariationId is 2363166.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002958.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYK	NM_002958.4	MANE Select	c.973A>C	p.Ile325Leu	missense	Exon 8 of 15	NP_002949.2	P34925-1
	RYK	NM_001005861.3		c.982A>C	p.Ile328Leu	missense	Exon 8 of 15	NP_001005861.1	P34925-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYK	ENST00000623711.4	TSL:1 MANE Select	c.973A>C	p.Ile325Leu	missense	Exon 8 of 15	ENSP00000485095.1	P34925-1
	RYK	ENST00000620660.4	TSL:1	c.982A>C	p.Ile328Leu	missense	Exon 8 of 15	ENSP00000478721.1	P34925-2
	RYK	ENST00000946535.1		c.1039A>C	p.Ile347Leu	missense	Exon 9 of 16	ENSP00000616594.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	-	1	RYK-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.94	T
PhyloP100		3.2
PrimateAI	Uncertain	0.53	T
Sift4G	Uncertain	0.020	D
Vest4		0.50
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
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs1425051712; hg19: chr3-133910735;