rs16907720

Variant names:

• chr9-91737515-A-G
• rs16907720
• NM_004560.4:c.498T>C

Your query was ambiguous. Multiple possible variants found:

• chr9-91737515-A-G
• chr9-91737515-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004560.4(ROR2):​c.498T>C​(p.Asp166Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0619 in 1,614,098 control chromosomes in the GnomAD database, including 3,888 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (825 hom., cov: 33)
  • Exomes 𝑓: 0.059 (3063 hom.)
• Consequence: ROR2 NM_004560.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.89
• Publications: 8 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-91737515-A-G is Benign according to our data. Variant chr9-91737515-A-G is described in ClinVar as Benign. ClinVar VariationId is 159820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR2	NM_004560.4	MANE Select	c.498T>C	p.Asp166Asp	synonymous	Exon 5 of 9	NP_004551.2
	ROR2	NM_001318204.2		c.498T>C	p.Asp166Asp	synonymous	Exon 5 of 8	NP_001305133.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR2	ENST00000375708.4	TSL:1 MANE Select	c.498T>C	p.Asp166Asp	synonymous	Exon 5 of 9	ENSP00000364860.3
	ROR2	ENST00000375715.5	TSL:1	c.78T>C	p.Asp26Asp	synonymous	Exon 5 of 13	ENSP00000364867.1
	ROR2	ENST00000550066.5	TSL:2	n.966T>C		non_coding_transcript_exon	Exon 7 of 11

Frequencies

GnomAD3 genomes AF: 0.0863 AC: 13128 AN: 152120 Hom.: 821 Cov.: 33

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0586

Gnomad ASJ AF: 0.0729

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0405

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0616

Gnomad OTH AF: 0.0800

GnomAD2 exomes AF: 0.0558 AC: 14026 AN: 251448 AF XY: 0.0527

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.0366

Gnomad ASJ exome AF: 0.0728

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0433

Gnomad NFE exome AF: 0.0646

Gnomad OTH exome AF: 0.0600

GnomAD4 exome AF: 0.0593 AC: 86683 AN: 1461860 Hom.: 3063 Cov.: 34 AF XY: 0.0578 AC XY: 42039 AN XY: 727232

African (AFR) AF: 0.177 AC: 5925 AN: 33480

American (AMR) AF: 0.0392 AC: 1752 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0723 AC: 1890 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0172 AC: 1487 AN: 86256

European-Finnish (FIN) AF: 0.0450 AC: 2404 AN: 53408

Middle Eastern (MID) AF: 0.0872 AC: 503 AN: 5768

European-Non Finnish (NFE) AF: 0.0618 AC: 68724 AN: 1111996

Other (OTH) AF: 0.0662 AC: 3995 AN: 60392

GnomAD4 genome AF: 0.0864 AC: 13152 AN: 152238 Hom.: 825 Cov.: 33 AF XY: 0.0828 AC XY: 6162 AN XY: 74448

African (AFR) AF: 0.170 AC: 7058 AN: 41506

American (AMR) AF: 0.0585 AC: 895 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0729 AC: 253 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4826

European-Finnish (FIN) AF: 0.0405 AC: 430 AN: 10618

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0617 AC: 4194 AN: 68008

Other (OTH) AF: 0.0791 AC: 167 AN: 2110

Alfa AF: 0.0738 Hom.: 823

Bravo AF: 0.0929

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.0671

EpiControl AF: 0.0683

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive Robinow syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Brachydactyly type B1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.13
DANN	Benign	0.51
PhyloP100		-1.9
Mutation Taster		=98/2	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: rs16907720; hg19: chr9-94499797;