NM_004560.4:c.1386+408G>A

Variant names:

• chr9-91726133-C-T
• rs4073735
• NM_004560.4:c.1386+408G>A

Variant summary

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

The NM_004560.4(ROR2):​c.1386+408G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 152,014 control chromosomes in the GnomAD database, including 21,938 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 0.52 (21938 hom., cov: 32)
• Consequence: ROR2 NM_004560.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.184
• 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)
• 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROR2	NM_004560.4	c.1386+408G>A		intron_variant	Intron 8 of 8	ENST00000375708.4	NP_004551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROR2	ENST00000375708.4	c.1386+408G>A		intron_variant	Intron 8 of 8	1	NM_004560.4	ENSP00000364860.3
ROR2	ENST00000375715.5	c.966+408G>A		intron_variant	Intron 8 of 12	1		ENSP00000364867.1
ROR2	ENST00000550066.5	n.1854+408G>A		intron_variant	Intron 10 of 10	2

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79485 AN: 151896 Hom.: 21886 Cov.: 32

Gnomad AFR AF: 0.696

Gnomad AMI AF: 0.460

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.572

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.520

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

GnomAD4 genome AF: 0.524 AC: 79595 AN: 152014 Hom.: 21938 Cov.: 32 AF XY: 0.522 AC XY: 38747 AN XY: 74282

African (AFR) AF: 0.696 AC: 28871 AN: 41470

American (AMR) AF: 0.428 AC: 6545 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 1496 AN: 3470

East Asian (EAS) AF: 0.550 AC: 2836 AN: 5158

South Asian (SAS) AF: 0.572 AC: 2758 AN: 4818

European-Finnish (FIN) AF: 0.418 AC: 4400 AN: 10536

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 30974 AN: 67970

Other (OTH) AF: 0.525 AC: 1108 AN: 2112

Alfa AF: 0.475 Hom.: 30267

Bravo AF: 0.531

Asia WGS AF: 0.598 AC: 2082 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.1
DANN	Benign	0.30
PhyloP100		-0.18
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: rs4073735; hg19: chr9-94488415;