9-91723482-G-T

Variant names:

• chr9-91723482-G-T
• rs542396423
• NM_004560.4:c.*180C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004560.4(ROR2):​c.*180C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000238 in 841,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: ROR2 NM_004560.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.455
• 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), 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.*180C>A		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.*180C>A		3_prime_UTR	Exon 9 of 9	ENSP00000364860.3	Q01974
	ROR2	ENST00000375715.5	TSL:1	c.1920+672C>A		intron	N/A	ENSP00000364867.1	B1APY4
	ROR2	ENST00000964760.1		c.*180C>A		3_prime_UTR	Exon 9 of 9	ENSP00000634819.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000238 AC: 2 AN: 841574 Hom.: 0 Cov.: 11 AF XY: 0.00000235 AC XY: 1 AN XY: 425834

African (AFR) AF: 0.0000985 AC: 2 AN: 20306

American (AMR) AF: 0.00 AC: 0 AN: 23784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16398

East Asian (EAS) AF: 0.00 AC: 0 AN: 34840

South Asian (SAS) AF: 0.00 AC: 0 AN: 56880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32656

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 614826

Other (OTH) AF: 0.00 AC: 0 AN: 39130

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	-0.84
CADD	Benign	0.16
DANN	Benign	0.75
PhyloP100		-0.46

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: rs542396423; hg19: chr9-94485764;