chr3-134222543-G-C

Position:

• chr3-134222543-G-C

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.233-4C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,580,678 control chromosomes in the GnomAD database, including 75 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 0.012 (50 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (25 hom.)
• Consequence: RYK NM_002958.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.621

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 (BayesDel_noAF=-0.76).
• BP6: Variant 3-134222543-G-C is Benign according to our data. Variant chr3-134222543-G-C is described in ClinVar as [Benign]. Clinvar id is 786021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0123 (1866/151940) while in subpopulation AFR AF= 0.0431 (1787/41460). AF 95% confidence interval is 0.0414. There are 50 homozygotes in gnomad4. There are 854 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1866 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYK	NM_002958.4	c.233-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000623711.4	NP_002949.2
RYK	NM_001005861.3	c.233-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001005861.1
RYK	XR_007095716.1	n.438-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYK	ENST00000623711.4	c.233-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002958.4	ENSP00000485095	A2
RYK	ENST00000620660.4	c.233-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000478721	P4

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1866 AN: 151822 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.0432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00289

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0106

GnomAD3 exomes AF: 0.00334 AC: 722 AN: 216076 Hom.: 21 AF XY: 0.00252 AC XY: 294 AN XY: 116896

Gnomad AFR exome AF: 0.0477

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000386

Gnomad FIN exome AF: 0.0000496

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.00119 AC: 1699 AN: 1428738 Hom.: 25 Cov.: 28 AF XY: 0.00106 AC XY: 751 AN XY: 709804

Gnomad4 AFR exome AF: 0.0436

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000612

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.0000805

Gnomad4 OTH exome AF: 0.00191

GnomAD4 genome AF: 0.0123 AC: 1866 AN: 151940 Hom.: 50 Cov.: 32 AF XY: 0.0115 AC XY: 854 AN XY: 74286

Gnomad4 AFR AF: 0.0431

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00130 Hom.: 1

Bravo AF: 0.0137

Asia WGS AF: 0.00173 AC: 6 AN: 3478

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	14
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs116266774; hg19: chr3-133941387;