NM_004560.4:c.*712C>T

Variant names:

• chr9-91722950-G-A
• rs1135150
• NM_004560.4:c.*712C>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.*712C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0643 in 214,182 control chromosomes in the GnomAD database, including 613 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (439 hom., cov: 33)
  • Exomes 𝑓: 0.067 (174 hom.)
• Consequence: ROR2 NM_004560.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.126
• Publications: 6 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=-0.8).
• BP6: Variant 9-91722950-G-A is Benign according to our data. Variant chr9-91722950-G-A is described in ClinVar as Benign. ClinVar VariationId is 367484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.14 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.*712C>T		3_prime_UTR	Exon 9 of 9	NP_004551.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR2	ENST00000375708.4	TSL:1 MANE Select	c.*712C>T		3_prime_UTR	Exon 9 of 9	ENSP00000364860.3
	ROR2	ENST00000375715.5	TSL:1	c.1921-370C>T		intron	N/A	ENSP00000364867.1
	ROR2	ENST00000964760.1		c.*712C>T		3_prime_UTR	Exon 9 of 9	ENSP00000634819.1

Frequencies

GnomAD3 genomes AF: 0.0629 AC: 9572 AN: 152066 Hom.: 433 Cov.: 33

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0936

Gnomad ASJ AF: 0.0571

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0672

Gnomad OTH AF: 0.0772

GnomAD4 exome AF: 0.0674 AC: 4178 AN: 61998 Hom.: 174 Cov.: 0 AF XY: 0.0689 AC XY: 2182 AN XY: 31684

African (AFR) AF: 0.0127 AC: 38 AN: 2998

American (AMR) AF: 0.0974 AC: 375 AN: 3850

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 107 AN: 2352

East Asian (EAS) AF: 0.127 AC: 637 AN: 5016

South Asian (SAS) AF: 0.0877 AC: 221 AN: 2520

European-Finnish (FIN) AF: 0.0942 AC: 258 AN: 2740

Middle Eastern (MID) AF: 0.0652 AC: 18 AN: 276

European-Non Finnish (NFE) AF: 0.0596 AC: 2297 AN: 38520

Other (OTH) AF: 0.0609 AC: 227 AN: 3726

GnomAD4 genome AF: 0.0630 AC: 9589 AN: 152184 Hom.: 439 Cov.: 33 AF XY: 0.0668 AC XY: 4974 AN XY: 74408

African (AFR) AF: 0.0147 AC: 612 AN: 41544

American (AMR) AF: 0.0937 AC: 1433 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0571 AC: 198 AN: 3466

East Asian (EAS) AF: 0.149 AC: 770 AN: 5182

South Asian (SAS) AF: 0.108 AC: 523 AN: 4824

European-Finnish (FIN) AF: 0.117 AC: 1240 AN: 10564

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0672 AC: 4572 AN: 67994

Other (OTH) AF: 0.0849 AC: 179 AN: 2108

Alfa AF: 0.0655 Hom.: 456

Bravo AF: 0.0574

Asia WGS AF: 0.147 AC: 509 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive Robinow syndrome (1)
-	-	1	Brachydactyly type B1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.3
DANN	Benign	0.73
PhyloP100		-0.13
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: rs1135150; hg19: chr9-94485232; COSMIC: COSV65217648;