rs10820900

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_004560.4(ROR2):c.733A>G(p.Thr245Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 1,611,554 control chromosomes in the GnomAD database, including 337,026 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 33496 hom., cov: 34)

Exomes 𝑓: 0.64 ( 303530 hom. )

Consequence

ROR2
NM_004560.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.604

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 -18 ACMG points.

PM1

In a domain FZ (size 134) in uniprot entity ROR2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_004560.4

BP4

Computational evidence support a benign effect (MetaRNN=1.0994917E-5).

BP6

Variant 9-91733326-T-C is Benign according to our data. Variant chr9-91733326-T-C is described in ClinVar as [Benign]. Clinvar id is 159821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-91733326-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROR2	NM_004560.4 link	c.733A>G	p.Thr245Ala	missense_variant	Exon 6 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.733A>G	p.Thr245Ala	missense_variant	Exon 6 of 9	1	NM_004560.4	ENSP00000364860.3	Q01974
ROR2	ENST00000375715.5 link	c.313A>G	p.Thr105Ala	missense_variant	Exon 6 of 13	1		ENSP00000364867.1	B1APY4
ROR2	ENST00000550066.5 link	n.1201A>G		non_coding_transcript_exon_variant	Exon 8 of 11	2

Frequencies

GnomAD3 genomes

AF:

0.661

AC:

100420

AN:

152002

Hom.:

33462

Cov.:

show subpopulations

Gnomad AFR

AF:

0.745

Gnomad AMI

AF:

0.695

Gnomad AMR

AF:

0.574

Gnomad ASJ

AF:

0.662

Gnomad EAS

AF:

0.514

Gnomad SAS

AF:

0.677

Gnomad FIN

AF:

0.613

Gnomad MID

AF:

0.570

Gnomad NFE

AF:

0.647

Gnomad OTH

AF:

0.626

GnomAD3 exomes

AF:

0.620

AC:

152549

AN:

246044

Hom.:

48081

AF XY:

0.626

AC XY:

83728

AN XY:

133676

show subpopulations

Gnomad AFR exome

AF:

0.746

Gnomad AMR exome

AF:

0.487

Gnomad ASJ exome

AF:

0.665

Gnomad EAS exome

AF:

0.476

Gnomad SAS exome

AF:

0.677

Gnomad FIN exome

AF:

0.617

Gnomad NFE exome

AF:

0.647

Gnomad OTH exome

AF:

0.626

GnomAD4 exome

AF:

0.644

AC:

939191

AN:

1459434

Hom.:

303530

Cov.:

AF XY:

0.645

AC XY:

468188

AN XY:

726020

show subpopulations

Gnomad4 AFR exome

AF:

0.755

Gnomad4 AMR exome

AF:

0.501

Gnomad4 ASJ exome

AF:

0.664

Gnomad4 EAS exome

AF:

0.512

Gnomad4 SAS exome

AF:

0.679

Gnomad4 FIN exome

AF:

0.620

Gnomad4 NFE exome

AF:

0.648

Gnomad4 OTH exome

AF:

0.650

GnomAD4 genome

AF:

0.661

AC:

100507

AN:

152120

Hom.:

33496

Cov.:

AF XY:

0.657

AC XY:

48870

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.745

Gnomad4 AMR

AF:

0.574

Gnomad4 ASJ

AF:

0.662

Gnomad4 EAS

AF:

0.513

Gnomad4 SAS

AF:

0.676

Gnomad4 FIN

AF:

0.613

Gnomad4 NFE

AF:

0.647

Gnomad4 OTH

AF:

0.622

Alfa

AF:

0.648

Hom.:

20600

Bravo

AF:

0.657

TwinsUK

AF:

0.657

AC:

2435

ALSPAC

AF:

0.646

AC:

2488

ESP6500AA

AF:

0.743

AC:

3275

ESP6500EA

AF:

0.646

AC:

5554

ExAC

AF:

0.627

AC:

75914

Asia WGS

AF:

0.593

AC:

2061

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 09, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Jul 26, 2018

GeneDx

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive Robinow syndrome

Benign:2

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. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brachydactyly type B1

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.066

T;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.025

T;T

MetaRNN

Benign

0.000011

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.35

.;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.32

N;N

REVEL

Benign

0.095

Sift

Benign

0.85

T;T

Sift4G

Benign

0.93

T;T

Polyphen

0.0

B;B

Vest4

0.015

MPC

0.20

ClinPred

0.00046

GERP RS

3.5

Varity_R

0.048

gMVP

0.47

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

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