NM_004560.4:c.1710G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004560.4(ROR2):c.1710G>A(p.Pro570Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0369 in 1,611,576 control chromosomes in the GnomAD database, including 1,234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 86 hom., cov: 33)

Exomes 𝑓: 0.038 ( 1148 hom. )

Consequence

ROR2
NM_004560.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -3.38

Publications

5 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 9-91724784-C-T is Benign according to our data. Variant chr9-91724784-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.38 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0273 (4161/152300) while in subpopulation NFE AF = 0.0431 (2933/68020). AF 95% confidence interval is 0.0418. There are 86 homozygotes in GnomAd4. There are 1998 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 86 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROR2	NM_004560.4 link	c.1710G>A	p.Pro570Pro	synonymous_variant	Exon 9 of 9	ENST00000375708.4	NP_004551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ROR2	ENST00000375708.4 link	c.1710G>A	p.Pro570Pro	synonymous_variant	Exon 9 of 9	1	NM_004560.4	ENSP00000364860.3
ROR2	ENST00000375715.5 link	c.1290G>A	p.Pro430Pro	synonymous_variant	Exon 9 of 13	1		ENSP00000364867.1
ROR2	ENST00000550066.5 link	n.2178G>A		non_coding_transcript_exon_variant	Exon 11 of 11	2

Frequencies

GnomAD3 genomes

AF:

0.0273

AC:

4159

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00729

Gnomad AMI

AF:

0.0746

Gnomad AMR

AF:

0.0194

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0159

Gnomad FIN

AF:

0.0393

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0431

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.0274

AC:

6847

AN:

250032

AF XY:

0.0280

show subpopulations

Gnomad AFR exome

AF:

0.00629

Gnomad AMR exome

AF:

0.0122

Gnomad ASJ exome

AF:

0.00650

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0396

Gnomad NFE exome

AF:

0.0416

Gnomad OTH exome

AF:

0.0239

GnomAD4 exome

AF:

0.0379

AC:

55361

AN:

1459276

Hom.:

1148

Cov.:

AF XY:

0.0371

AC XY:

26891

AN XY:

725408

show subpopulations

African (AFR)

AF:

0.00583

AC:

195

AN:

33448

American (AMR)

AF:

0.0116

AC:

519

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00652

AC:

170

AN:

26078

East Asian (EAS)

AF:

0.000101

AC:

AN:

39628

South Asian (SAS)

AF:

0.0182

AC:

1572

AN:

86204

European-Finnish (FIN)

AF:

0.0380

AC:

2020

AN:

53150

Middle Eastern (MID)

AF:

0.0163

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0440

AC:

48829

AN:

1110038

Other (OTH)

AF:

0.0325

AC:

1958

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

3616

7231

10847

14462

18078

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1790

3580

5370

7160

8950

<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:

0.0273

AC:

4161

AN:

152300

Hom.:

Cov.:

AF XY:

0.0268

AC XY:

1998

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00727

AC:

302

AN:

41566

American (AMR)

AF:

0.0195

AC:

298

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00547

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.0162

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0393

AC:

417

AN:

10618

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0431

AC:

2933

AN:

68020

Other (OTH)

AF:

0.0199

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

206

411

617

822

1028

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.0352

Hom.:

206

Bravo

AF:

0.0244

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0355

EpiControl

AF:

0.0373

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely 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

- -

Sep 16, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

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

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.21

(source)

DANN

Benign

0.74

PhyloP100

-3.4

Mutation Taster

=100/0

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