rs1135150

Positions:

• chr9-91722950-G-A

Variant summary

Our verdict is Benign. Variant got -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:3
• Conservation: PhyloP100: -0.126

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROR2	NM_004560.4	c.*712C>T		3_prime_UTR_variant	9/9	ENST00000375708.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROR2	ENST00000375708.4	c.*712C>T		3_prime_UTR_variant	9/9	1	NM_004560.4	P1
ROR2	ENST00000375715.5	c.1921-370C>T		intron_variant		1
ROR2	ENST00000550066.5	n.4012C>T		non_coding_transcript_exon_variant	11/11	2

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

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.0974

Gnomad4 ASJ exome AF: 0.0455

Gnomad4 EAS exome AF: 0.127

Gnomad4 SAS exome AF: 0.0877

Gnomad4 FIN exome AF: 0.0942

Gnomad4 NFE exome AF: 0.0596

Gnomad4 OTH exome AF: 0.0609

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

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.0937

Gnomad4 ASJ AF: 0.0571

Gnomad4 EAS AF: 0.149

Gnomad4 SAS AF: 0.108

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.0672

Gnomad4 OTH AF: 0.0849

Alfa AF: 0.0661 Hom.: 349

Bravo AF: 0.0574

Asia WGS AF: 0.147 AC: 509 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive Robinow syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Brachydactyly type B1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.3
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs1135150; hg19: chr9-94485232; COSMIC: COSV65217648;