rs10761129

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004560.4(ROR2):c.2455G>A(p.Val819Ile) variant causes a missense change. The variant allele was found at a frequency of 0.687 in 1,611,526 control chromosomes in the GnomAD database, including 383,045 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.72 ( 39170 hom., cov: 33)

Exomes 𝑓: 0.68 ( 343875 hom. )

Consequence

ROR2
NM_004560.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 4.94

Publications

42 publications found

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 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

ROR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.5631723E-7).

BP6

Variant 9-91724039-C-T is Benign according to our data. Variant chr9-91724039-C-T is described in ClinVar as Benign. ClinVar VariationId is 159818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROR2	NM_004560.4 link	c.2455G>A	p.Val819Ile	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.2455G>A	p.Val819Ile	missense_variant	Exon 9 of 9	1	NM_004560.4	ENSP00000364860.3	Q01974
ROR2	ENST00000375715.5 link	c.1920+115G>A		intron_variant	Intron 9 of 12	1		ENSP00000364867.1	B1APY4
ROR2	ENST00000550066.5 link	n.2923G>A		non_coding_transcript_exon_variant	Exon 11 of 11	2

Frequencies

GnomAD3 genomes

AF:

0.715

AC:

108682

AN:

152008

Hom.:

39118

Cov.:

show subpopulations

Gnomad AFR

AF:

0.755

Gnomad AMI

AF:

0.670

Gnomad AMR

AF:

0.766

Gnomad ASJ

AF:

0.609

Gnomad EAS

AF:

0.926

Gnomad SAS

AF:

0.612

Gnomad FIN

AF:

0.748

Gnomad MID

AF:

0.684

Gnomad NFE

AF:

0.672

Gnomad OTH

AF:

0.694

GnomAD2 exomes

AF:

0.716

AC:

177373

AN:

247598

AF XY:

0.703

show subpopulations

Gnomad AFR exome

AF:

0.760

Gnomad AMR exome

AF:

0.847

Gnomad ASJ exome

AF:

0.610

Gnomad EAS exome

AF:

0.926

Gnomad FIN exome

AF:

0.744

Gnomad NFE exome

AF:

0.669

Gnomad OTH exome

AF:

0.693

GnomAD4 exome

AF:

0.684

AC:

997906

AN:

1459400

Hom.:

343875

Cov.:

AF XY:

0.681

AC XY:

494077

AN XY:

726020

show subpopulations

African (AFR)

AF:

0.765

AC:

25622

AN:

33472

American (AMR)

AF:

0.838

AC:

37477

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.613

AC:

16004

AN:

26114

East Asian (EAS)

AF:

0.946

AC:

37547

AN:

39700

South Asian (SAS)

AF:

0.617

AC:

53171

AN:

86222

European-Finnish (FIN)

AF:

0.735

AC:

37670

AN:

51270

Middle Eastern (MID)

AF:

0.644

AC:

3716

AN:

5766

European-Non Finnish (NFE)

AF:

0.670

AC:

745204

AN:

1111772

Other (OTH)

AF:

0.687

AC:

41495

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

22272

44545

66817

89090

111362

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19394

38788

58182

77576

96970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.715

AC:

108792

AN:

152126

Hom.:

39170

Cov.:

AF XY:

0.719

AC XY:

53494

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.756

AC:

31381

AN:

41526

American (AMR)

AF:

0.766

AC:

11714

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.609

AC:

2113

AN:

3470

East Asian (EAS)

AF:

0.926

AC:

4768

AN:

5148

South Asian (SAS)

AF:

0.612

AC:

2952

AN:

4824

European-Finnish (FIN)

AF:

0.748

AC:

7925

AN:

10600

Middle Eastern (MID)

AF:

0.677

AC:

199

AN:

294

European-Non Finnish (NFE)

AF:

0.672

AC:

45661

AN:

67954

Other (OTH)

AF:

0.696

AC:

1469

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1607

3213

4820

6426

8033

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

832

1664

2496

3328

4160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.685

Hom.:

102445

Bravo

AF:

0.721

TwinsUK

AF:

0.679

AC:

2518

ALSPAC

AF:

0.665

AC:

2562

ESP6500AA

AF:

0.760

AC:

3350

ESP6500EA

AF:

0.670

AC:

5761

ExAC

AF:

0.709

AC:

86005

Asia WGS

AF:

0.762

AC:

2651

AN:

3478

EpiCase

AF:

0.662

EpiControl

AF:

0.663

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 13, 2016

Eurofins Ntd Llc (ga)

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive Robinow syndrome

Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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:2

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal dominant Robinow syndrome 1

Benign:1

May 28, 2019

Mendelics

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

0.044

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.097

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.51

MetaRNN

Benign

8.6e-7

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.9

PhyloP100

4.9

PrimateAI

Uncertain

0.75

PROVEAN

Benign

0.29

REVEL

Benign

0.24

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.065

MPC

0.17

ClinPred

0.00039

GERP RS

3.4

Varity_R

0.026

gMVP

0.060

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over