chr9-91755433-C-A

Variant names:

• chr9-91755433-C-A
• rs4467996
• NM_004560.4:c.494+638G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004560.4(ROR2):​c.494+638G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.629 in 152,192 control chromosomes in the GnomAD database, including 30,399 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.63 (30399 hom., cov: 34)
• Consequence: ROR2 NM_004560.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.546
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.705 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.494+638G>T		intron	N/A	NP_004551.2
	ROR2	NM_001318204.2		c.494+638G>T		intron	N/A	NP_001305133.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR2	ENST00000375708.4	TSL:1 MANE Select	c.494+638G>T		intron	N/A	ENSP00000364860.3	Q01974
	ROR2	ENST00000375715.5	TSL:1	c.74+638G>T		intron	N/A	ENSP00000364867.1	B1APY4
	ROR2	ENST00000964760.1		c.494+638G>T		intron	N/A	ENSP00000634819.1

Frequencies

GnomAD3 genomes AF: 0.629 AC: 95655 AN: 152074 Hom.: 30363 Cov.: 34

Gnomad AFR AF: 0.712

Gnomad AMI AF: 0.526

Gnomad AMR AF: 0.661

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.613

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.633

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.587

Gnomad OTH AF: 0.610

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.629 AC: 95747 AN: 152192 Hom.: 30399 Cov.: 34 AF XY: 0.629 AC XY: 46810 AN XY: 74402

African (AFR) AF: 0.712 AC: 29570 AN: 41522

American (AMR) AF: 0.661 AC: 10104 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 1922 AN: 3472

East Asian (EAS) AF: 0.612 AC: 3167 AN: 5176

South Asian (SAS) AF: 0.510 AC: 2460 AN: 4822

European-Finnish (FIN) AF: 0.633 AC: 6713 AN: 10598

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.587 AC: 39894 AN: 67988

Other (OTH) AF: 0.610 AC: 1290 AN: 2116

Alfa AF: 0.588 Hom.: 39546

Bravo AF: 0.636

Asia WGS AF: 0.554 AC: 1924 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.1
DANN	Benign	0.40
PhyloP100		0.55
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: rs4467996; hg19: chr9-94517715;