chr3-134250504-G-A

Position:

• chr3-134250504-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002958.4(RYK):​c.151C>T​(p.Arg51Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,268,614 control chromosomes in the GnomAD database, including 269 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (16 hom., cov: 30)
  • Exomes 𝑓: 0.019 (253 hom.)
• Consequence: RYK NM_002958.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.204

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004956633).
• BP6: Variant 3-134250504-G-A is Benign according to our data. Variant chr3-134250504-G-A is described in ClinVar as [Benign]. Clinvar id is 781973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.013 (1965/151492) while in subpopulation NFE AF= 0.0184 (1245/67746). AF 95% confidence interval is 0.0175. There are 16 homozygotes in gnomad4. There are 958 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1965 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYK	NM_002958.4	c.151C>T	p.Arg51Trp	missense_variant	1/15	ENST00000623711.4	NP_002949.2
RYK	NM_001005861.3	c.151C>T	p.Arg51Trp	missense_variant	1/15		NP_001005861.1
RYK	XR_007095716.1	n.356C>T		non_coding_transcript_exon_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYK	ENST00000623711.4	c.151C>T	p.Arg51Trp	missense_variant	1/15	1	NM_002958.4	ENSP00000485095	A2
RYK	ENST00000620660.4	c.151C>T	p.Arg51Trp	missense_variant	1/15	1		ENSP00000478721	P4

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1964 AN: 151386 Hom.: 16 Cov.: 30

Gnomad AFR AF: 0.00334

Gnomad AMI AF: 0.0505

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0275

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0184

Gnomad OTH AF: 0.0111

GnomAD3 exomes AF: 0.0200 AC: 394 AN: 19676 Hom.: 9 AF XY: 0.0181 AC XY: 224 AN XY: 12356

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.0162

Gnomad ASJ exome AF: 0.0331

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00270

Gnomad FIN exome AF: 0.0338

Gnomad NFE exome AF: 0.0249

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0194 AC: 21697 AN: 1117122 Hom.: 253 Cov.: 27 AF XY: 0.0191 AC XY: 10280 AN XY: 538526

Gnomad4 AFR exome AF: 0.00290

Gnomad4 AMR exome AF: 0.0118

Gnomad4 ASJ exome AF: 0.0212

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00142

Gnomad4 FIN exome AF: 0.0277

Gnomad4 NFE exome AF: 0.0211

Gnomad4 OTH exome AF: 0.0158

GnomAD4 genome AF: 0.0130 AC: 1965 AN: 151492 Hom.: 16 Cov.: 30 AF XY: 0.0129 AC XY: 958 AN XY: 74042

Gnomad4 AFR AF: 0.00333

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0275

Gnomad4 NFE AF: 0.0184

Gnomad4 OTH AF: 0.0110

Alfa AF: 0.0113 Hom.: 4

Bravo AF: 0.0126

ExAC AF: 0.00772 AC: 182

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Uncertain	0.98
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.60	T;T
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	0.99	N
PrimateAI	Pathogenic	0.87	D
Sift4G	Uncertain	0.045	D;D
Vest4		0.25
ClinPred		0.043	T
GERP RS		-0.031
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.0
Varity_R		0.14
gMVP		0.33

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: rs201505334; hg19: chr3-133969348; COSMIC: COSV56063483; COSMIC: COSV56063483;