rs73654047

Variant names:

• chr9-91722926-T-C
• rs73654047
• NM_004560.4:c.*736A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_004560.4(ROR2):​c.*736A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00422 in 282,858 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: ROR2 NM_004560.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.899
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 9-91722926-T-C is Benign according to our data. Variant chr9-91722926-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 367483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00653 (995/152364) while in subpopulation AFR AF = 0.022 (915/41586). AF 95% confidence interval is 0.0208. There are 13 homozygotes in GnomAd4. There are 463 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR,AD gene

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.*736A>G		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.*736A>G		3_prime_UTR	Exon 9 of 9	ENSP00000364860.3	Q01974
	ROR2	ENST00000375715.5	TSL:1	c.1921-346A>G		intron	N/A	ENSP00000364867.1	B1APY4
	ROR2	ENST00000964760.1		c.*736A>G		3_prime_UTR	Exon 9 of 9	ENSP00000634819.1

Frequencies

GnomAD3 genomes AF: 0.00652 AC: 993 AN: 152246 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000264

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.00152 AC: 199 AN: 130494 Hom.: 2 Cov.: 0 AF XY: 0.00141 AC XY: 94 AN XY: 66684

African (AFR) AF: 0.0241 AC: 141 AN: 5858

American (AMR) AF: 0.00170 AC: 12 AN: 7056

Ashkenazi Jewish (ASJ) AF: 0.000439 AC: 2 AN: 4552

East Asian (EAS) AF: 0.00 AC: 0 AN: 10406

South Asian (SAS) AF: 0.000336 AC: 3 AN: 8926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5584

Middle Eastern (MID) AF: 0.00163 AC: 1 AN: 612

European-Non Finnish (NFE) AF: 0.000264 AC: 21 AN: 79656

Other (OTH) AF: 0.00242 AC: 19 AN: 7844

GnomAD4 genome AF: 0.00653 AC: 995 AN: 152364 Hom.: 13 Cov.: 33 AF XY: 0.00621 AC XY: 463 AN XY: 74508

African (AFR) AF: 0.0220 AC: 915 AN: 41586

American (AMR) AF: 0.00288 AC: 44 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68046

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00388 Hom.: 1

Bravo AF: 0.00767

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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: rs73654047; hg19: chr9-94485208;