NM_004560.4:c.494+8208C>T

Variant names:

• chr9-91747863-G-A
• rs16907725
• NM_004560.4:c.494+8208C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004560.4(ROR2):​c.494+8208C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 152,108 control chromosomes in the GnomAD database, including 2,677 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2677 hom., cov: 32)
• Consequence: ROR2 NM_004560.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.912
• Publications: 3 publications found

Genes affected

ROR2 (HGNC:10257): (receptor tyrosine kinase like orphan receptor 2) The protein encoded by this gene is a receptor protein tyrosine kinase and type I transmembrane protein that belongs to the ROR subfamily of cell surface receptors. The protein may be involved in the early formation of the chondrocytes and may be required for cartilage and growth plate development. Mutations in this gene can cause brachydactyly type B, a skeletal disorder characterized by hypoplasia/aplasia of distal phalanges and nails. In addition, mutations in this gene can cause the autosomal recessive form of Robinow syndrome, which is characterized by skeletal dysplasia with generalized limb bone shortening, segmental defects of the spine, brachydactyly, and a dysmorphic facial appearance. [provided by RefSeq, Jul 2008]

ROR2 Gene-Disease associations (from GenCC):

• brachydactyly type B1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive Robinow syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROR2	NM_004560.4	c.494+8208C>T		intron_variant	Intron 4 of 8	ENST00000375708.4	NP_004551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROR2	ENST00000375708.4	c.494+8208C>T		intron_variant	Intron 4 of 8	1	NM_004560.4	ENSP00000364860.3
ROR2	ENST00000375715.5	c.74+8208C>T		intron_variant	Intron 4 of 12	1		ENSP00000364867.1
ROR2	ENST00000550066.5	n.962+8208C>T		intron_variant	Intron 6 of 10	2

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26175 AN: 151988 Hom.: 2669 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.244

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.0979

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.164

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.172 AC: 26222 AN: 152108 Hom.: 2677 Cov.: 32 AF XY: 0.176 AC XY: 13061 AN XY: 74374

African (AFR) AF: 0.258 AC: 10701 AN: 41494

American (AMR) AF: 0.205 AC: 3138 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 423 AN: 3470

East Asian (EAS) AF: 0.262 AC: 1356 AN: 5166

South Asian (SAS) AF: 0.293 AC: 1408 AN: 4812

European-Finnish (FIN) AF: 0.0979 AC: 1036 AN: 10584

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7524 AN: 67996

Other (OTH) AF: 0.169 AC: 357 AN: 2108

Alfa AF: 0.133 Hom.: 2401

Bravo AF: 0.180

Asia WGS AF: 0.297 AC: 1033 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.27
DANN	Benign	0.42
PhyloP100		-0.91
Mutation Taster		=100/0	polymorphism (auto)

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: rs16907725; hg19: chr9-94510145; COSMIC: COSV65218299;