9-91722776-C-A

Variant names:

• chr9-91722776-C-A
• rs114078962
• NM_004560.4:c.*886G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004560.4(ROR2):​c.*886G>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 0.00256 in 600,982 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0066 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: ROR2 NM_004560.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.00
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 9-91722776-C-A is Benign according to our data. Variant chr9-91722776-C-A is described in ClinVar as Benign. ClinVar VariationId is 367481.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00657 (1001/152274) while in subpopulation AFR AF = 0.0216 (898/41548). AF 95% confidence interval is 0.0204. There are 8 homozygotes in GnomAd4. There are 483 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.*886G>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.*886G>T		3_prime_UTR	Exon 9 of 9	ENSP00000364860.3	Q01974
	ROR2	ENST00000375715.5	TSL:1	c.1921-196G>T		intron	N/A	ENSP00000364867.1	B1APY4
	ROR2	ENST00000964760.1		c.*886G>T		3_prime_UTR	Exon 9 of 9	ENSP00000634819.1

Frequencies

GnomAD3 genomes AF: 0.00659 AC: 1002 AN: 152156 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.00120 AC: 539 AN: 448708 Hom.: 2 Cov.: 0 AF XY: 0.00111 AC XY: 262 AN XY: 235528

African (AFR) AF: 0.0221 AC: 283 AN: 12814

American (AMR) AF: 0.00234 AC: 49 AN: 20972

Ashkenazi Jewish (ASJ) AF: 0.00365 AC: 51 AN: 13964

East Asian (EAS) AF: 0.00 AC: 0 AN: 30940

South Asian (SAS) AF: 0.000133 AC: 6 AN: 45098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30596

Middle Eastern (MID) AF: 0.00177 AC: 6 AN: 3388

European-Non Finnish (NFE) AF: 0.000215 AC: 57 AN: 264786

Other (OTH) AF: 0.00333 AC: 87 AN: 26150

GnomAD4 genome AF: 0.00657 AC: 1001 AN: 152274 Hom.: 8 Cov.: 33 AF XY: 0.00649 AC XY: 483 AN XY: 74464

African (AFR) AF: 0.0216 AC: 898 AN: 41548

American (AMR) AF: 0.00399 AC: 61 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68032

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00176 Hom.: 0

Bravo AF: 0.00739

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	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	-0.93
CADD	Benign	0.058
DANN	Benign	0.48
PhyloP100		-1.0
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: rs114078962; hg19: chr9-94485058; COSMIC: COSV65218524;