rs55983376

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1045C>G(p.His349Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00361 in 1,614,150 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. H349H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.018 ( 104 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 85 hom. )

Consequence

ROR2
NM_004560.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.52

Publications

7 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), PanelApp Australia
autosomal recessive Robinow syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics

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=0.0043153763).

BP6

Variant 9-91731048-G-C is Benign according to our data. Variant chr9-91731048-G-C is described in ClinVar as Benign. ClinVar VariationId is 159810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0612 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR2	NM_004560.4	MANE Select	c.1045C>G	p.His349Asp	missense	Exon 7 of 9	NP_004551.2
	ROR2	NM_001318204.2		c.1045C>G	p.His349Asp	missense	Exon 7 of 8	NP_001305133.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ROR2	ENST00000375708.4	TSL:1 MANE Select	c.1045C>G	p.His349Asp	missense	Exon 7 of 9	ENSP00000364860.3	Q01974
ROR2	ENST00000375715.5	TSL:1	c.625C>G	p.His209Asp	missense	Exon 7 of 13	ENSP00000364867.1	B1APY4
ROR2	ENST00000964760.1		c.964C>G	p.His322Asp	missense	Exon 7 of 9	ENSP00000634819.1

Frequencies

GnomAD3 genomes

AF:

0.0183

AC:

2789

AN:

152160

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0633

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00642

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.00503

AC:

1265

AN:

251428

AF XY:

0.00373

show subpopulations

Gnomad AFR exome

AF:

0.0666

Gnomad AMR exome

AF:

0.00309

Gnomad ASJ exome

AF:

0.00318

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00207

AC:

3033

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

1373

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0688

AC:

2303

AN:

33480

American (AMR)

AF:

0.00351

AC:

157

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00298

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000156

AC:

174

AN:

1112012

Other (OTH)

AF:

0.00432

AC:

261

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

210

421

631

842

1052

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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:

0.0184

AC:

2795

AN:

152278

Hom.:

104

Cov.:

AF XY:

0.0175

AC XY:

1305

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0633

AC:

2628

AN:

41540

American (AMR)

AF:

0.00641

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00104

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

68018

Other (OTH)

AF:

0.0123

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

135

270

405

540

675

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00105

Hom.:

Bravo

AF:

0.0207

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0572

AC:

252

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00609

AC:

740

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000474

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Autosomal recessive Robinow syndrome (1)

Brachydactyly type B1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.070

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.49

MetaRNN

Benign

0.0043

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.42

PhyloP100

1.5

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.94

REVEL

Benign

0.056

Sift

Benign

0.46

Sift4G

Benign

0.62

Polyphen

0.0

Vest4

0.37

MVP

0.68

MPC

0.29

ClinPred

0.0030

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.37

gMVP

0.63

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over