rs34431454

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBA1

The NM_004560.4(ROR2):c.2083G>A(p.Gly695Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,614,146 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 98 hom. )

Consequence

ROR2
NM_004560.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.82

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.011894673).

BP6

Variant 9-91724411-C-T is Benign according to our data. Variant chr9-91724411-C-T is described in ClinVar as [Benign]. Clinvar id is 159814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-91724411-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROR2	NM_004560.4 link	c.2083G>A	p.Gly695Arg	missense_variant	Exon 9 of 9	ENST00000375708.4	NP_004551.2	Q01974

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ROR2	ENST00000375708.4 link	c.2083G>A	p.Gly695Arg	missense_variant	Exon 9 of 9	1	NM_004560.4	ENSP00000364860.3	Q01974
ROR2	ENST00000375715.5 link	c.1663G>A	p.Gly555Arg	missense_variant	Exon 9 of 13	1		ENSP00000364867.1	B1APY4
ROR2	ENST00000550066.5 link	n.2551G>A		non_coding_transcript_exon_variant	Exon 11 of 11	2

Frequencies

GnomAD3 genomes

AF:

0.00250

AC:

380

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.0591

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00470

AC:

1181

AN:

251224

Hom.:

AF XY:

0.00413

AC XY:

561

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.0572

Gnomad SAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000343

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00216

AC:

3160

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00213

AC XY:

1550

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00203

Gnomad4 EAS exome

AF:

0.0670

Gnomad4 SAS exome

AF:

0.00169

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000152

Gnomad4 OTH exome

AF:

0.00194

GnomAD4 genome

AF:

0.00248

AC:

377

AN:

152304

Hom.:

Cov.:

AF XY:

0.00301

AC XY:

224

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.0590

Gnomad4 SAS

AF:

0.00248

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00259

Hom.:

Bravo

AF:

0.00285

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00477

AC:

579

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Feb 06, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.056

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.65

D;D

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

D;D

MetaRNN

Benign

0.012

T;T

MetaSVM

Uncertain

0.049

MutationAssessor

Uncertain

2.4

.;M

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.7

D;D

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.94

MutPred

0.45

.;Gain of solvent accessibility (P = 0.0471);

MVP

0.95

MPC

0.88

ClinPred

0.093

GERP RS

4.7

Varity_R

0.75

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over