9-91737336-G-A

Variant names:

• chr9-91737336-G-A
• rs7855522
• NM_004560.4:c.622+55C>T

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.622+55C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 1,610,388 control chromosomes in the GnomAD database, including 182,563 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14623 hom., cov: 32)
  • Exomes 𝑓: 0.48 (167940 hom.)
• Consequence: ROR2 NM_004560.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.60
• Publications: 8 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)
• autosomal recessive Robinow syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-91737336-G-A is Benign according to our data. Variant chr9-91737336-G-A is described in ClinVar as Benign. ClinVar VariationId is 1236286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.483 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR2	NM_004560.4	MANE Select	c.622+55C>T		intron	N/A	NP_004551.2
	ROR2	NM_001318204.2		c.622+55C>T		intron	N/A	NP_001305133.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR2	ENST00000375708.4	TSL:1 MANE Select	c.622+55C>T		intron	N/A	ENSP00000364860.3
	ROR2	ENST00000375715.5	TSL:1	c.202+55C>T		intron	N/A	ENSP00000364867.1
	ROR2	ENST00000550066.5	TSL:2	n.1090+55C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65202 AN: 151918 Hom.: 14623 Cov.: 32

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.443

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.483

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.517

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.488

Gnomad OTH AF: 0.420

GnomAD4 exome AF: 0.478 AC: 697136 AN: 1458352 Hom.: 167940 AF XY: 0.477 AC XY: 346137 AN XY: 725692

African (AFR) AF: 0.297 AC: 9921 AN: 33416

American (AMR) AF: 0.408 AC: 18260 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 12744 AN: 26106

East Asian (EAS) AF: 0.479 AC: 18996 AN: 39674

South Asian (SAS) AF: 0.432 AC: 37252 AN: 86148

European-Finnish (FIN) AF: 0.511 AC: 26807 AN: 52482

Middle Eastern (MID) AF: 0.401 AC: 2303 AN: 5748

European-Non Finnish (NFE) AF: 0.489 AC: 542702 AN: 1109802

Other (OTH) AF: 0.467 AC: 28151 AN: 60274

GnomAD4 genome AF: 0.429 AC: 65206 AN: 152036 Hom.: 14623 Cov.: 32 AF XY: 0.430 AC XY: 31963 AN XY: 74308

African (AFR) AF: 0.304 AC: 12612 AN: 41466

American (AMR) AF: 0.427 AC: 6522 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 1677 AN: 3470

East Asian (EAS) AF: 0.462 AC: 2382 AN: 5160

South Asian (SAS) AF: 0.418 AC: 2016 AN: 4822

European-Finnish (FIN) AF: 0.517 AC: 5467 AN: 10568

Middle Eastern (MID) AF: 0.318 AC: 93 AN: 292

European-Non Finnish (NFE) AF: 0.488 AC: 33156 AN: 67962

Other (OTH) AF: 0.416 AC: 878 AN: 2112

Alfa AF: 0.450 Hom.: 2597

Bravo AF: 0.416

Asia WGS AF: 0.394 AC: 1369 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Oct 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.41
DANN	Benign	0.72
PhyloP100		-1.6
Mutation Taster		=100/0	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: rs7855522; hg19: chr9-94499618; COSMIC: COSV65216594;