rs10761129

Variant names:

• chr9-91724039-C-T
• rs10761129
• NM_004560.4:c.2455G>A

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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:11
• Conservation: PhyloP100: 4.94
• Publications: 42 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.2455G>A	p.Val819Ile	missense	Exon 9 of 9	NP_004551.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR2	ENST00000375708.4	TSL:1 MANE Select	c.2455G>A	p.Val819Ile	missense	Exon 9 of 9	ENSP00000364860.3	Q01974
	ROR2	ENST00000375715.5	TSL:1	c.1920+115G>A		intron	N/A	ENSP00000364867.1	B1APY4
	ROR2	ENST00000964760.1		c.2374G>A	p.Val792Ile	missense	Exon 9 of 9	ENSP00000634819.1

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

GnomAD2 exomes AF: 0.716 AC: 177373 AN: 247598 AF XY: 0.703

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 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

African (AFR) AF: 0.765 AC: 25622 AN: 33472

American (AMR) AF: 0.838 AC: 37477 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 16004 AN: 26114

East Asian (EAS) AF: 0.946 AC: 37547 AN: 39700

South Asian (SAS) AF: 0.617 AC: 53171 AN: 86222

European-Finnish (FIN) AF: 0.735 AC: 37670 AN: 51270

Middle Eastern (MID) AF: 0.644 AC: 3716 AN: 5766

European-Non Finnish (NFE) AF: 0.670 AC: 745204 AN: 1111772

Other (OTH) AF: 0.687 AC: 41495 AN: 60368

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

African (AFR) AF: 0.756 AC: 31381 AN: 41526

American (AMR) AF: 0.766 AC: 11714 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 2113 AN: 3470

East Asian (EAS) AF: 0.926 AC: 4768 AN: 5148

South Asian (SAS) AF: 0.612 AC: 2952 AN: 4824

European-Finnish (FIN) AF: 0.748 AC: 7925 AN: 10600

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.672 AC: 45661 AN: 67954

Other (OTH) AF: 0.696 AC: 1469 AN: 2110

Alfa AF: 0.685 Hom.: 102445

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Autosomal recessive Robinow syndrome (2)
-	-	2	Brachydactyly type B1 (2)
-	-	1	Autosomal dominant Robinow syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.9
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10761129; hg19: chr9-94486321; COSMIC: COSV104686845;