rs10820900

Variant names:

• chr9-91733326-T-C
• rs10820900
• NM_004560.4:c.733A>G

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.733A>G​(p.Thr245Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 1,611,554 control chromosomes in the GnomAD database, including 337,026 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33496 hom., cov: 34)
  • Exomes 𝑓: 0.64 (303530 hom.)
• Consequence: ROR2 NM_004560.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.604
• Publications: 43 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=1.0994917E-5).
• BP6: Variant 9-91733326-T-C is Benign according to our data. Variant chr9-91733326-T-C is described in ClinVar as Benign. ClinVar VariationId is 159821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.738 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.733A>G	p.Thr245Ala	missense	Exon 6 of 9	NP_004551.2
	ROR2	NM_001318204.2		c.733A>G	p.Thr245Ala	missense	Exon 6 of 8	NP_001305133.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR2	ENST00000375708.4	TSL:1 MANE Select	c.733A>G	p.Thr245Ala	missense	Exon 6 of 9	ENSP00000364860.3	Q01974
	ROR2	ENST00000375715.5	TSL:1	c.313A>G	p.Thr105Ala	missense	Exon 6 of 13	ENSP00000364867.1	B1APY4
	ROR2	ENST00000964760.1		c.733A>G	p.Thr245Ala	missense	Exon 6 of 9	ENSP00000634819.1

Frequencies

GnomAD3 genomes AF: 0.661 AC: 100420 AN: 152002 Hom.: 33462 Cov.: 34

Gnomad AFR AF: 0.745

Gnomad AMI AF: 0.695

Gnomad AMR AF: 0.574

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.677

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.626

GnomAD2 exomes AF: 0.620 AC: 152549 AN: 246044 AF XY: 0.626

Gnomad AFR exome AF: 0.746

Gnomad AMR exome AF: 0.487

Gnomad ASJ exome AF: 0.665

Gnomad EAS exome AF: 0.476

Gnomad FIN exome AF: 0.617

Gnomad NFE exome AF: 0.647

Gnomad OTH exome AF: 0.626

GnomAD4 exome AF: 0.644 AC: 939191 AN: 1459434 Hom.: 303530 Cov.: 80 AF XY: 0.645 AC XY: 468188 AN XY: 726020

African (AFR) AF: 0.755 AC: 25261 AN: 33462

American (AMR) AF: 0.501 AC: 22335 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 17334 AN: 26088

East Asian (EAS) AF: 0.512 AC: 20305 AN: 39648

South Asian (SAS) AF: 0.679 AC: 58451 AN: 86106

European-Finnish (FIN) AF: 0.620 AC: 32349 AN: 52184

Middle Eastern (MID) AF: 0.641 AC: 3696 AN: 5764

European-Non Finnish (NFE) AF: 0.648 AC: 720235 AN: 1111322

Other (OTH) AF: 0.650 AC: 39225 AN: 60318

GnomAD4 genome AF: 0.661 AC: 100507 AN: 152120 Hom.: 33496 Cov.: 34 AF XY: 0.657 AC XY: 48870 AN XY: 74368

African (AFR) AF: 0.745 AC: 30939 AN: 41510

American (AMR) AF: 0.574 AC: 8780 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 2297 AN: 3468

East Asian (EAS) AF: 0.513 AC: 2642 AN: 5146

South Asian (SAS) AF: 0.676 AC: 3256 AN: 4816

European-Finnish (FIN) AF: 0.613 AC: 6501 AN: 10600

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.647 AC: 43983 AN: 67966

Other (OTH) AF: 0.622 AC: 1312 AN: 2110

Alfa AF: 0.647 Hom.: 28322

Bravo AF: 0.657

TwinsUK AF: 0.657 AC: 2435

ALSPAC AF: 0.646 AC: 2488

ESP6500AA AF: 0.743 AC: 3275

ESP6500EA AF: 0.646 AC: 5554

ExAC AF: 0.627 AC: 75914

Asia WGS AF: 0.593 AC: 2061 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Autosomal recessive Robinow syndrome (2)
-	-	2	Brachydactyly type B1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	14
DANN	Benign	0.76
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.025	T
MetaRNN	Benign	0.000011	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.35	N
PhyloP100		0.60
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.095
Sift	Benign	0.85	T
Sift4G	Benign	0.93	T
Polyphen		0.0	B
Vest4		0.015
MPC		0.20
ClinPred		0.00046	T
GERP RS		3.5
Varity_R		0.048
gMVP		0.47
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: rs10820900; hg19: chr9-94495608; COSMIC: COSV65216750;