3-134191843-A-C

Position:

• chr3-134191843-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002958.4(RYK):​c.1015+6T>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,598,274 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0091 (6 hom., cov: 32)
  • Exomes 𝑓: 0.013 (157 hom.)
• Consequence: RYK NM_002958.4 splice_donor_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.53

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 3-134191843-A-C is Benign according to our data. Variant chr3-134191843-A-C is described in ClinVar as [Benign]. Clinvar id is 2654162.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0132 (19047/1445940) while in subpopulation MID AF= 0.0206 (118/5730). AF 95% confidence interval is 0.0176. There are 157 homozygotes in gnomad4_exome. There are 9236 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1384 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYK	NM_002958.4	c.1015+6T>G		splice_donor_region_variant, intron_variant		ENST00000623711.4	NP_002949.2
RYK	NM_001005861.3	c.1024+6T>G		splice_donor_region_variant, intron_variant			NP_001005861.1
RYK	XR_007095716.1	n.1229+6T>G		splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYK	ENST00000623711.4	c.1015+6T>G		splice_donor_region_variant, intron_variant		1	NM_002958.4	ENSP00000485095	A2
RYK	ENST00000620660.4	c.1024+6T>G		splice_donor_region_variant, intron_variant		1		ENSP00000478721	P4
RYK	ENST00000486725.1	c.68+6T>G		splice_donor_region_variant, intron_variant, NMD_transcript_variant		2		ENSP00000417836
RYK	ENST00000480381.1	n.384+6T>G		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00910 AC: 1385 AN: 152216 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.0101 AC: 2377 AN: 235792 Hom.: 17 AF XY: 0.0101 AC XY: 1290 AN XY: 127898

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00864

Gnomad ASJ exome AF: 0.00740

Gnomad EAS exome AF: 0.0000582

Gnomad SAS exome AF: 0.00719

Gnomad FIN exome AF: 0.00521

Gnomad NFE exome AF: 0.0151

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0132 AC: 19047 AN: 1445940 Hom.: 157 Cov.: 29 AF XY: 0.0129 AC XY: 9236 AN XY: 718406

Gnomad4 AFR exome AF: 0.00236

Gnomad4 AMR exome AF: 0.00818

Gnomad4 ASJ exome AF: 0.00891

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00727

Gnomad4 FIN exome AF: 0.00628

Gnomad4 NFE exome AF: 0.0150

Gnomad4 OTH exome AF: 0.0127

GnomAD4 genome AF: 0.00909 AC: 1384 AN: 152334 Hom.: 6 Cov.: 32 AF XY: 0.00889 AC XY: 662 AN XY: 74500

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.0124

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.0139

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0114 Hom.: 2

Bravo AF: 0.00908

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

RYK: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	17
DANN	Benign	0.83

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: rs55965934; hg19: chr3-133910687;