rs16907720

Positions:

• chr9-91737515-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 159820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-91737515-A-G is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROR2	NM_004560.4	c.498T>C	p.Asp166Asp	synonymous_variant	5/9	ENST00000375708.4	NP_004551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROR2	ENST00000375708.4	c.498T>C	p.Asp166Asp	synonymous_variant	5/9	1	NM_004560.4	ENSP00000364860.3
ROR2	ENST00000375715.5	c.78T>C	p.Asp26Asp	synonymous_variant	5/13	1		ENSP00000364867.1
ROR2	ENST00000550066.5	n.966T>C		non_coding_transcript_exon_variant	7/11	2

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

GnomAD3 exomes AF: 0.0558 AC: 14026 AN: 251448 Hom.: 606 AF XY: 0.0527 AC XY: 7161 AN XY: 135902

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 SAS exome AF: 0.0178

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

Gnomad4 AFR exome AF: 0.177

Gnomad4 AMR exome AF: 0.0392

Gnomad4 ASJ exome AF: 0.0723

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0172

Gnomad4 FIN exome AF: 0.0450

Gnomad4 NFE exome AF: 0.0618

Gnomad4 OTH exome AF: 0.0662

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

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.0585

Gnomad4 ASJ AF: 0.0729

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0174

Gnomad4 FIN AF: 0.0405

Gnomad4 NFE AF: 0.0617

Gnomad4 OTH AF: 0.0791

Alfa AF: 0.0704 Hom.: 594

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Autosomal recessive Robinow syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.13
DANN	Benign	0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs16907720; hg19: chr9-94499797;