rs10761129

Positions:

• chr9-91724039-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 13/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.94

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
ROR2	NM_004560.4	c.2455G>A	p.Val819Ile	missense_variant	9/9	ENST00000375708.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROR2	ENST00000375708.4	c.2455G>A	p.Val819Ile	missense_variant	9/9	1	NM_004560.4	P1
ROR2	ENST00000375715.5	c.1920+115G>A		intron_variant		1
ROR2	ENST00000550066.5	n.2923G>A		non_coding_transcript_exon_variant	11/11	2

Frequencies

GnomAD3 genomes AF: 0.715 AC: 108682 AN: 152008 Hom.: 39118 Cov.: 33

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

GnomAD3 exomes AF: 0.716 AC: 177373 AN: 247598 Hom.: 64746 AF XY: 0.703 AC XY: 94327 AN XY: 134168

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 SAS exome AF: 0.615

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.: 97 AF XY: 0.681 AC XY: 494077 AN XY: 726020

Gnomad4 AFR exome AF: 0.765

Gnomad4 AMR exome AF: 0.838

Gnomad4 ASJ exome AF: 0.613

Gnomad4 EAS exome AF: 0.946

Gnomad4 SAS exome AF: 0.617

Gnomad4 FIN exome AF: 0.735

Gnomad4 NFE exome AF: 0.670

Gnomad4 OTH exome AF: 0.687

GnomAD4 genome AF: 0.715 AC: 108792 AN: 152126 Hom.: 39170 Cov.: 33 AF XY: 0.719 AC XY: 53494 AN XY: 74366

Gnomad4 AFR AF: 0.756

Gnomad4 AMR AF: 0.766

Gnomad4 ASJ AF: 0.609

Gnomad4 EAS AF: 0.926

Gnomad4 SAS AF: 0.612

Gnomad4 FIN AF: 0.748

Gnomad4 NFE AF: 0.672

Gnomad4 OTH AF: 0.696

Alfa AF: 0.677 Hom.: 68852

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2016	- -

Autosomal recessive Robinow syndrome Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Brachydactyly type B1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2018	- -

Autosomal dominant Robinow syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.39
DEOGEN2	Benign	0.097	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	8.6e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.9	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.24
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.065
MPC		0.17
ClinPred		0.00039	T
GERP RS		3.4
Varity_R		0.026
gMVP		0.060

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

Other links and lift over

dbSNP: rs10761129; hg19: chr9-94486321;