chr3-134191843-A-C

Variant names:

• chr3-134191843-A-C
• rs55965934
• NM_002958.4:c.1015+6T>G

Variant summary

Our verdict is Benign. The variant received -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 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. 1/1 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.53
• Publications: 4 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 -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 VariationId is 2654162.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 9236 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1384 AD gene.

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.1015+6T>G		splice_region intron	N/A	NP_002949.2	P34925-1
	RYK	NM_001005861.3		c.1024+6T>G		splice_region intron	N/A	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.1015+6T>G		splice_region intron	N/A	ENSP00000485095.1	P34925-1
	RYK	ENST00000620660.4	TSL:1	c.1024+6T>G		splice_region intron	N/A	ENSP00000478721.1	P34925-2
	RYK	ENST00000946535.1		c.1081+6T>G		splice_region intron	N/A	ENSP00000616594.1

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

GnomAD2 exomes AF: 0.0101 AC: 2377 AN: 235792 AF XY: 0.0101

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 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

African (AFR) AF: 0.00236 AC: 77 AN: 32684

American (AMR) AF: 0.00818 AC: 340 AN: 41560

Ashkenazi Jewish (ASJ) AF: 0.00891 AC: 230 AN: 25814

East Asian (EAS) AF: 0.00 AC: 0 AN: 39262

South Asian (SAS) AF: 0.00727 AC: 596 AN: 81928

European-Finnish (FIN) AF: 0.00628 AC: 334 AN: 53176

Middle Eastern (MID) AF: 0.0206 AC: 118 AN: 5730

European-Non Finnish (NFE) AF: 0.0150 AC: 16589 AN: 1105898

Other (OTH) AF: 0.0127 AC: 763 AN: 59888

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

African (AFR) AF: 0.00250 AC: 104 AN: 41582

American (AMR) AF: 0.0124 AC: 190 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00835 AC: 29 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4830

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10616

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0139 AC: 943 AN: 68018

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0120 Hom.: 20

Bravo AF: 0.00908

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	17
DANN	Benign	0.83
PhyloP100		1.5
Mutation Taster		=99/1	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: rs55965934; hg19: chr3-133910687;