rs7863557

Variant names:

• chr9-91775833-C-G
• rs7863557
• NM_004560.4:c.98-15G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004560.4(ROR2):​c.98-15G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,610,440 control chromosomes in the GnomAD database, including 50,607 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4175 hom., cov: 32)
  • Exomes 𝑓: 0.25 (46432 hom.)
• Consequence: ROR2 NM_004560.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0310
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-91775833-C-G is Benign according to our data. Variant chr9-91775833-C-G is described in ClinVar as Benign. ClinVar VariationId is 159823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004560.4. 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
	ROR2	NM_004560.4	MANE Select	c.98-15G>C		intron	N/A	NP_004551.2
	ROR2	NM_001318204.2		c.98-15G>C		intron	N/A	NP_001305133.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR2	ENST00000375708.4	TSL:1 MANE Select	c.98-15G>C		intron	N/A	ENSP00000364860.3
	ROR2	ENST00000375715.5	TSL:1	c.-323-15G>C		intron	N/A	ENSP00000364867.1
	ROR2	ENST00000964760.1		c.98-15G>C		intron	N/A	ENSP00000634819.1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34611 AN: 151976 Hom.: 4164 Cov.: 32

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.0624

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.237

GnomAD2 exomes AF: 0.221 AC: 55302 AN: 250208 AF XY: 0.228

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.0612

Gnomad FIN exome AF: 0.195

Gnomad NFE exome AF: 0.265

Gnomad OTH exome AF: 0.250

GnomAD4 exome AF: 0.246 AC: 359414 AN: 1458346 Hom.: 46432 Cov.: 31 AF XY: 0.248 AC XY: 180225 AN XY: 725660

African (AFR) AF: 0.218 AC: 7299 AN: 33418

American (AMR) AF: 0.128 AC: 5715 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 7900 AN: 26116

East Asian (EAS) AF: 0.0382 AC: 1516 AN: 39676

South Asian (SAS) AF: 0.256 AC: 22018 AN: 86124

European-Finnish (FIN) AF: 0.203 AC: 10827 AN: 53380

Middle Eastern (MID) AF: 0.378 AC: 2171 AN: 5748

European-Non Finnish (NFE) AF: 0.259 AC: 286717 AN: 1108964

Other (OTH) AF: 0.253 AC: 15251 AN: 60246

GnomAD4 genome AF: 0.228 AC: 34656 AN: 152094 Hom.: 4175 Cov.: 32 AF XY: 0.223 AC XY: 16545 AN XY: 74348

African (AFR) AF: 0.210 AC: 8723 AN: 41478

American (AMR) AF: 0.185 AC: 2827 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1063 AN: 3472

East Asian (EAS) AF: 0.0624 AC: 323 AN: 5180

South Asian (SAS) AF: 0.254 AC: 1221 AN: 4816

European-Finnish (FIN) AF: 0.189 AC: 2002 AN: 10570

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17653 AN: 67974

Other (OTH) AF: 0.236 AC: 497 AN: 2110

Alfa AF: 0.256 Hom.: 930

Bravo AF: 0.225

Asia WGS AF: 0.193 AC: 673 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Autosomal recessive Robinow syndrome (2)
-	-	2	Brachydactyly type B1 (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.0
DANN	Benign	0.51
PhyloP100		-0.031
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: rs7863557; hg19: chr9-94538115; COSMIC: COSV65216647; COSMIC: COSV65216647;