rs12554679

Variant names:

• chr9-91898833-G-A
• rs12554679
• NM_004560.4:c.97+51034C>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.97+51034C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 152,176 control chromosomes in the GnomAD database, including 2,438 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 0.16 (2438 hom., cov: 33)
• Consequence: ROR2 NM_004560.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.48
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROR2	NM_004560.4	c.97+51034C>T		intron_variant	Intron 1 of 8	ENST00000375708.4	NP_004551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROR2	ENST00000375708.4	c.97+51034C>T		intron_variant	Intron 1 of 8	1	NM_004560.4	ENSP00000364860.3
ROR2	ENST00000375715.5	c.-324+49774C>T		intron_variant	Intron 1 of 12	1		ENSP00000364867.1
ROR2	ENST00000495386.5	n.235-15450C>T		intron_variant	Intron 2 of 4	3
ROR2	ENST00000546883.1	n.299+24932C>T		intron_variant	Intron 2 of 3	3

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24485 AN: 152058 Hom.: 2431 Cov.: 33

Gnomad AFR AF: 0.0374

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.166

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

GnomAD4 genome AF: 0.161 AC: 24483 AN: 152176 Hom.: 2438 Cov.: 33 AF XY: 0.161 AC XY: 11985 AN XY: 74388

African (AFR) AF: 0.0373 AC: 1550 AN: 41548

American (AMR) AF: 0.259 AC: 3956 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 598 AN: 3466

East Asian (EAS) AF: 0.167 AC: 864 AN: 5168

South Asian (SAS) AF: 0.161 AC: 775 AN: 4828

European-Finnish (FIN) AF: 0.172 AC: 1820 AN: 10568

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14300 AN: 67984

Other (OTH) AF: 0.164 AC: 346 AN: 2112

Alfa AF: 0.167 Hom.: 373

Bravo AF: 0.165

Asia WGS AF: 0.163 AC: 566 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.54
DANN	Benign	0.77
PhyloP100		-2.5
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: rs12554679; hg19: chr9-94661115; COSMIC: COSV65218064;