chr9-91723486-GCTCT-G

Variant names:

• chr9-91723486-GCTCT-G
• rs140581955
• NM_004560.4:c.*172_*175delAGAG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004560.4(ROR2):​c.*172_*175delAGAG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 1,056,250 control chromosomes in the GnomAD database, including 95,333 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (12960 hom., cov: 0)
  • Exomes 𝑓: 0.43 (82373 hom.)
• Consequence: ROR2 NM_004560.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.383
• 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), 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 -16 ACMG points.

• BP6: Variant 9-91723486-GCTCT-G is Benign according to our data. Variant chr9-91723486-GCTCT-G is described in ClinVar as Benign. ClinVar VariationId is 367493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.478 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.*172_*175delAGAG		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.*172_*175delAGAG		3_prime_UTR	Exon 9 of 9	ENSP00000364860.3	Q01974
	ROR2	ENST00000375715.5	TSL:1	c.1920+664_1920+667delAGAG		intron	N/A	ENSP00000364867.1	B1APY4
	ROR2	ENST00000964760.1		c.*172_*175delAGAG		3_prime_UTR	Exon 9 of 9	ENSP00000634819.1

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62253 AN: 151520 Hom.: 12962 Cov.: 0

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.396

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.399

GnomAD4 exome AF: 0.427 AC: 386419 AN: 904612 Hom.: 82373 AF XY: 0.423 AC XY: 192723 AN XY: 455774

African (AFR) AF: 0.351 AC: 7535 AN: 21476

American (AMR) AF: 0.540 AC: 13734 AN: 25424

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 6342 AN: 16820

East Asian (EAS) AF: 0.448 AC: 15928 AN: 35566

South Asian (SAS) AF: 0.318 AC: 18586 AN: 58504

European-Finnish (FIN) AF: 0.440 AC: 14522 AN: 33028

Middle Eastern (MID) AF: 0.286 AC: 813 AN: 2840

European-Non Finnish (NFE) AF: 0.436 AC: 292039 AN: 669858

Other (OTH) AF: 0.412 AC: 16920 AN: 41096

GnomAD4 genome AF: 0.411 AC: 62256 AN: 151638 Hom.: 12960 Cov.: 0 AF XY: 0.410 AC XY: 30393 AN XY: 74080

African (AFR) AF: 0.347 AC: 14358 AN: 41348

American (AMR) AF: 0.487 AC: 7423 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1306 AN: 3464

East Asian (EAS) AF: 0.422 AC: 2169 AN: 5138

South Asian (SAS) AF: 0.301 AC: 1447 AN: 4812

European-Finnish (FIN) AF: 0.442 AC: 4646 AN: 10512

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.437 AC: 29639 AN: 67824

Other (OTH) AF: 0.395 AC: 832 AN: 2106

Alfa AF: 0.427 Hom.: 1728

Bravo AF: 0.415

Asia WGS AF: 0.339 AC: 1178 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant Robinow syndrome 1 (1)
-	-	1	Brachydactyly (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.38
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: rs140581955; hg19: chr9-94485768; COSMIC: COSV65217226;