3-134250569-AGCGGCGGCG-AGCGGCG

Variant names:

• chr3-134250569-AGCG-A
• rs1284777873
• NM_002958.4:c.83_85delCGC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_002958.4(RYK):​c.83_85delCGC​(p.Pro28del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000641 in 1,074,086 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00074 (0 hom.)
• Consequence: RYK NM_002958.4 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_002958.4

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.83_85delCGC	p.Pro28del	disruptive_inframe_deletion	Exon 1 of 15	NP_002949.2	P34925-1
	RYK	NM_001005861.3		c.83_85delCGC	p.Pro28del	disruptive_inframe_deletion	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.83_85delCGC	p.Pro28del	disruptive_inframe_deletion	Exon 1 of 15	ENSP00000485095.1	P34925-1
	RYK	ENST00000620660.4	TSL:1	c.83_85delCGC	p.Pro28del	disruptive_inframe_deletion	Exon 1 of 15	ENSP00000478721.1	P34925-2
	RYK	ENST00000946535.1		c.83_85delCGC	p.Pro28del	disruptive_inframe_deletion	Exon 1 of 16	ENSP00000616594.1

Frequencies

GnomAD3 genomes AF: 0.00000674 AC: 1 AN: 148408 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 30 AF XY: 0.00

Gnomad NFE exome AF: 0.00

GnomAD4 exome AF: 0.000743 AC: 688 AN: 925570 Hom.: 0 AF XY: 0.000719 AC XY: 315 AN XY: 438378

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000718 AC: 13 AN: 18106

American (AMR) AF: 0.000165 AC: 1 AN: 6056

Ashkenazi Jewish (ASJ) AF: 0.000558 AC: 6 AN: 10748

East Asian (EAS) AF: 0.000476 AC: 10 AN: 21026

South Asian (SAS) AF: 0.000578 AC: 10 AN: 17290

European-Finnish (FIN) AF: 0.000395 AC: 7 AN: 17738

Middle Eastern (MID) AF: 0.000416 AC: 1 AN: 2404

European-Non Finnish (NFE) AF: 0.000776 AC: 618 AN: 796554

Other (OTH) AF: 0.000617 AC: 22 AN: 35648

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000673 AC: 1 AN: 148516 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 1 AN XY: 72412

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40994

American (AMR) AF: 0.00 AC: 0 AN: 14990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.000109 AC: 1 AN: 9214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66726

Other (OTH) AF: 0.00 AC: 0 AN: 2070

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=300/0	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: rs1284777873; hg19: chr3-133969413;