Genetic Variant NM_004560.4:c.98-15G>C (chr9-91775833-C-G) – ACMG Classification: Benign (-20 pts)

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.98-15G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,610,440 control chromosomes in the GnomAD database, including 50,607 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4175 hom., cov: 32)

Exomes 𝑓: 0.25 ( 46432 hom. )

Consequence

ROR2
NM_004560.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0310

Publications

10 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 (BayesDel_noAF=-0.81).

BP6

Variant 9-91775833-C-G is Benign according to our data. Variant chr9-91775833-C-G is described in ClinVar as Benign. ClinVar VariationId is 159823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.256 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.98-15G>C		intron	N/A	NP_004551.2
	ROR2	NM_001318204.2		c.98-15G>C		intron	N/A	NP_001305133.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ROR2	ENST00000375708.4	TSL:1 MANE Select	c.98-15G>C	intron	N/A	ENSP00000364860.3	Q01974
ROR2	ENST00000375715.5	TSL:1	c.-323-15G>C	intron	N/A	ENSP00000364867.1	B1APY4
ROR2	ENST00000964760.1		c.98-15G>C	intron	N/A	ENSP00000634819.1

Frequencies

GnomAD3 genomes

AF:

0.228

AC:

34611

AN:

151976

Hom.:

4164

Cov.:

show subpopulations

Gnomad AFR

AF:

0.210

Gnomad AMI

AF:

0.266

Gnomad AMR

AF:

0.185

Gnomad ASJ

AF:

0.306

Gnomad EAS

AF:

0.0624

Gnomad SAS

AF:

0.254

Gnomad FIN

AF:

0.189

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.260

Gnomad OTH

AF:

0.237

GnomAD2 exomes

AF:

0.221

AC:

55302

AN:

250208

AF XY:

0.228

show subpopulations

Gnomad AFR exome

AF:

0.210

Gnomad AMR exome

AF:

0.123

Gnomad ASJ exome

AF:

0.301

Gnomad EAS exome

AF:

0.0612

Gnomad FIN exome

AF:

0.195

Gnomad NFE exome

AF:

0.265

Gnomad OTH exome

AF:

0.250

GnomAD4 exome

AF:

0.246

AC:

359414

AN:

1458346

Hom.:

46432

Cov.:

AF XY:

0.248

AC XY:

180225

AN XY:

725660

show subpopulations

African (AFR)

AF:

0.218

AC:

7299

AN:

33418

American (AMR)

AF:

0.128

AC:

5715

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.302

AC:

7900

AN:

26116

East Asian (EAS)

AF:

0.0382

AC:

1516

AN:

39676

South Asian (SAS)

AF:

0.256

AC:

22018

AN:

86124

European-Finnish (FIN)

AF:

0.203

AC:

10827

AN:

53380

Middle Eastern (MID)

AF:

0.378

AC:

2171

AN:

5748

European-Non Finnish (NFE)

AF:

0.259

AC:

286717

AN:

1108964

Other (OTH)

AF:

0.253

AC:

15251

AN:

60246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

12657

25314

37971

50628

63285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9448

18896

28344

37792

47240

<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:

0.228

AC:

34656

AN:

152094

Hom.:

4175

Cov.:

AF XY:

0.223

AC XY:

16545

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.210

AC:

8723

AN:

41478

American (AMR)

AF:

0.185

AC:

2827

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.306

AC:

1063

AN:

3472

East Asian (EAS)

AF:

0.0624

AC:

323

AN:

5180

South Asian (SAS)

AF:

0.254

AC:

1221

AN:

4816

European-Finnish (FIN)

AF:

0.189

AC:

2002

AN:

10570

Middle Eastern (MID)

AF:

0.354

AC:

104

AN:

294

European-Non Finnish (NFE)

AF:

0.260

AC:

17653

AN:

67974

Other (OTH)

AF:

0.236

AC:

497

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1380

2759

4139

5518

6898

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

374

748

1122

1496

1870

<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:

0.256

Hom.:

930

Bravo

AF:

0.225

Asia WGS

AF:

0.193

AC:

673

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Autosomal recessive Robinow syndrome (2)

Brachydactyly type B1 (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

8.0

(source)

DANN

Benign

0.51

PhyloP100

-0.031

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over