rs139860270

Variant names:

• chr3-134250508-G-A
• rs139860270
• NM_002958.4:c.147C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-134250508-G-A
• chr3-134250508-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_002958.4(RYK):​c.147C>T​(p.Ala49Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,246,878 control chromosomes in the GnomAD database, including 14,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (1924 hom., cov: 30)
  • Exomes 𝑓: 0.13 (12161 hom.)
• Consequence: RYK NM_002958.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.831
• Publications: 5 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.051).
• BP6: Variant 3-134250508-G-A is Benign according to our data. Variant chr3-134250508-G-A is described in ClinVar as Benign. ClinVar VariationId is 3048012.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.831 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

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.147C>T	p.Ala49Ala	synonymous	Exon 1 of 15	NP_002949.2	P34925-1
	RYK	NM_001005861.3		c.147C>T	p.Ala49Ala	synonymous	Exon 1 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.147C>T	p.Ala49Ala	synonymous	Exon 1 of 15	ENSP00000485095.1	P34925-1
	RYK	ENST00000620660.4	TSL:1	c.147C>T	p.Ala49Ala	synonymous	Exon 1 of 15	ENSP00000478721.1	P34925-2
	RYK	ENST00000946535.1		c.147C>T	p.Ala49Ala	synonymous	Exon 1 of 16	ENSP00000616594.1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21692 AN: 151204 Hom.: 1911 Cov.: 30

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.0860

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.143

GnomAD2 exomes AF: 0.191 AC: 2838 AN: 14856 AF XY: 0.191

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.260

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.541

Gnomad FIN exome AF: 0.210

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.134 AC: 146474 AN: 1095566 Hom.: 12161 Cov.: 25 AF XY: 0.134 AC XY: 70341 AN XY: 526194

African (AFR) AF: 0.132 AC: 2968 AN: 22464

American (AMR) AF: 0.213 AC: 2060 AN: 9686

Ashkenazi Jewish (ASJ) AF: 0.0968 AC: 1442 AN: 14902

East Asian (EAS) AF: 0.520 AC: 13248 AN: 25472

South Asian (SAS) AF: 0.163 AC: 4564 AN: 27926

European-Finnish (FIN) AF: 0.143 AC: 3231 AN: 22554

Middle Eastern (MID) AF: 0.138 AC: 409 AN: 2964

European-Non Finnish (NFE) AF: 0.121 AC: 112006 AN: 926198

Other (OTH) AF: 0.151 AC: 6546 AN: 43400

GnomAD4 genome AF: 0.144 AC: 21719 AN: 151312 Hom.: 1924 Cov.: 30 AF XY: 0.147 AC XY: 10835 AN XY: 73942

African (AFR) AF: 0.132 AC: 5466 AN: 41386

American (AMR) AF: 0.186 AC: 2824 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.0860 AC: 298 AN: 3466

East Asian (EAS) AF: 0.476 AC: 2419 AN: 5086

South Asian (SAS) AF: 0.162 AC: 780 AN: 4824

European-Finnish (FIN) AF: 0.147 AC: 1513 AN: 10310

Middle Eastern (MID) AF: 0.140 AC: 41 AN: 292

European-Non Finnish (NFE) AF: 0.118 AC: 7979 AN: 67746

Other (OTH) AF: 0.147 AC: 308 AN: 2096

Alfa AF: 0.0490 Hom.: 47

Bravo AF: 0.147

Asia WGS AF: 0.322 AC: 1078 AN: 3358

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	RYK-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	12
DANN	Benign	0.94
PhyloP100		0.83
PromoterAI		0.0059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.0
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139860270; hg19: chr3-133969352; COSMIC: COSV56060517; COSMIC: COSV56060517;