rs9409652

Variant names:

• chr9-91738494-A-G
• rs9409652
• NM_004560.4:c.495-976T>C

Variant summary

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

The NM_004560.4(ROR2):​c.495-976T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 152,006 control chromosomes in the GnomAD database, including 18,579 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 0.48 (18579 hom., cov: 32)
• Consequence: ROR2 NM_004560.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0460
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROR2	NM_004560.4	c.495-976T>C		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.495-976T>C		intron_variant	Intron 4 of 8	1	NM_004560.4	ENSP00000364860.3
ROR2	ENST00000375715.5	c.75-976T>C		intron_variant	Intron 4 of 12	1		ENSP00000364867.1
ROR2	ENST00000550066.5	n.963-976T>C		intron_variant	Intron 6 of 10	2

Frequencies

GnomAD3 genomes AF: 0.481 AC: 73119 AN: 151888 Hom.: 18579 Cov.: 32

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.461

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.603

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.481

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

GnomAD4 genome AF: 0.481 AC: 73128 AN: 152006 Hom.: 18579 Cov.: 32 AF XY: 0.485 AC XY: 35995 AN XY: 74292

African (AFR) AF: 0.317 AC: 13156 AN: 41466

American (AMR) AF: 0.569 AC: 8700 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1974 AN: 3466

East Asian (EAS) AF: 0.461 AC: 2377 AN: 5158

South Asian (SAS) AF: 0.454 AC: 2191 AN: 4824

European-Finnish (FIN) AF: 0.603 AC: 6363 AN: 10550

Middle Eastern (MID) AF: 0.370 AC: 108 AN: 292

European-Non Finnish (NFE) AF: 0.542 AC: 36827 AN: 67934

Other (OTH) AF: 0.476 AC: 1008 AN: 2116

Alfa AF: 0.516 Hom.: 6393

Bravo AF: 0.472

Asia WGS AF: 0.417 AC: 1447 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.84
DANN	Benign	0.54
PhyloP100		0.046
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: rs9409652; hg19: chr9-94500776;