NM_004560.4:c.97+43416A>G

Variant names:

• chr9-91906451-T-C
• rs3905385
• NM_004560.4:c.97+43416A>G

Variant summary

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

The NM_004560.4(ROR2):​c.97+43416A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 152,044 control chromosomes in the GnomAD database, including 4,866 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 0.24 (4866 hom., cov: 32)
• Consequence: ROR2 NM_004560.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROR2	NM_004560.4	c.97+43416A>G		intron_variant	Intron 1 of 8	ENST00000375708.4	NP_004551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROR2	ENST00000375708.4	c.97+43416A>G		intron_variant	Intron 1 of 8	1	NM_004560.4	ENSP00000364860.3
ROR2	ENST00000375715.5	c.-324+42156A>G		intron_variant	Intron 1 of 12	1		ENSP00000364867.1
ROR2	ENST00000495386.5	n.234+17314A>G		intron_variant	Intron 2 of 4	3
ROR2	ENST00000546883.1	n.299+17314A>G		intron_variant	Intron 2 of 3	3

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35851 AN: 151926 Hom.: 4859 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.229

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

GnomAD4 genome AF: 0.236 AC: 35862 AN: 152044 Hom.: 4866 Cov.: 32 AF XY: 0.243 AC XY: 18072 AN XY: 74324

African (AFR) AF: 0.126 AC: 5242 AN: 41490

American (AMR) AF: 0.423 AC: 6454 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 847 AN: 3470

East Asian (EAS) AF: 0.376 AC: 1935 AN: 5152

South Asian (SAS) AF: 0.254 AC: 1221 AN: 4806

European-Finnish (FIN) AF: 0.274 AC: 2893 AN: 10564

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.243 AC: 16505 AN: 67992

Other (OTH) AF: 0.228 AC: 483 AN: 2116

Alfa AF: 0.226 Hom.: 6985

Bravo AF: 0.245

Asia WGS AF: 0.306 AC: 1064 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.24
DANN	Benign	0.73
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs3905385; hg19: chr9-94668733;