9-91731048-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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. 15/20 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:6

Conservation

PhyloP100: 1.52

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 disulfide_bond (size 40) in uniprot entity ROR2_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_004560.4

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 id is 159810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-91731048-G-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROR2	NM_004560.4 linkuse as main transcript	c.1045C>G	p.His349Asp	missense_variant	7/9	ENST00000375708.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ROR2	ENST00000375708.4 linkuse as main transcript	c.1045C>G	p.His349Asp	missense_variant	7/9	1	NM_004560.4	P1
ROR2	ENST00000375715.5 linkuse as main transcript	c.625C>G	p.His209Asp	missense_variant	7/13	1
ROR2	ENST00000550066.5 linkuse as main transcript	n.1513C>G		non_coding_transcript_exon_variant	9/11	2

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

GnomAD3 exomes

AF:

0.00503

AC:

1265

AN:

251428

Hom.:

AF XY:

0.00373

AC XY:

507

AN XY:

135914

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 SAS exome

AF:

0.000163

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

Gnomad4 AFR exome

AF:

0.0688

Gnomad4 AMR exome

AF:

0.00351

Gnomad4 ASJ exome

AF:

0.00298

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000156

Gnomad4 OTH exome

AF:

0.00432

GnomAD4 genome

AF:

0.0184

AC:

2795

AN:

152278

Hom.:

104

Cov.:

AF XY:

0.0175

AC XY:

1305

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0633

Gnomad4 AMR

AF:

0.00641

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.0123

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

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 28, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Autosomal recessive Robinow syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.49

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.070

T;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.49

T;T

MetaRNN

Benign

0.0043

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.87

D;D

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.94

N;N

REVEL

Benign

0.056

Sift

Benign

0.46

T;T

Sift4G

Benign

0.62

T;T

Polyphen

0.0

B;B

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

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