rs41277837

chr9-91724784-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004560.4(ROR2):c.1710G>A(p.Pro570=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0369 in 1,611,576 control chromosomes in the GnomAD database, including 1,234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (86 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1148 hom.)
• Consequence: ROR2 NM_004560.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.38

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 9-91724784-C-T is Benign according to our data. Variant chr9-91724784-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 159811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-91724784-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.38 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0273 (4161/152300) while in subpopulation NFE AF= 0.0431 (2933/68020). AF 95% confidence interval is 0.0418. There are 86 homozygotes in gnomad4. There are 1998 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 86 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROR2	NM_004560.4	c.1710G>A	p.Pro570=	synonymous_variant	9/9	ENST00000375708.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROR2	ENST00000375708.4	c.1710G>A	p.Pro570=	synonymous_variant	9/9	1	NM_004560.4	P1
ROR2	ENST00000375715.5	c.1290G>A	p.Pro430=	synonymous_variant	9/13	1
ROR2	ENST00000550066.5	n.2178G>A		non_coding_transcript_exon_variant	11/11	2

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4159 AN: 152182 Hom.: 86 Cov.: 33

Gnomad AFR AF: 0.00729

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0194

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.0393

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0431

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0274 AC: 6847 AN: 250032 Hom.: 139 AF XY: 0.0280 AC XY: 3785 AN XY: 135146

Gnomad AFR exome AF: 0.00629

Gnomad AMR exome AF: 0.0122

Gnomad ASJ exome AF: 0.00650

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0187

Gnomad FIN exome AF: 0.0396

Gnomad NFE exome AF: 0.0416

Gnomad OTH exome AF: 0.0239

GnomAD4 exome AF: 0.0379 AC: 55361 AN: 1459276 Hom.: 1148 Cov.: 43 AF XY: 0.0371 AC XY: 26891 AN XY: 725408

Gnomad4 AFR exome AF: 0.00583

Gnomad4 AMR exome AF: 0.0116

Gnomad4 ASJ exome AF: 0.00652

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0182

Gnomad4 FIN exome AF: 0.0380

Gnomad4 NFE exome AF: 0.0440

Gnomad4 OTH exome AF: 0.0325

GnomAD4 genome AF: 0.0273 AC: 4161 AN: 152300 Hom.: 86 Cov.: 33 AF XY: 0.0268 AC XY: 1998 AN XY: 74466

Gnomad4 AFR AF: 0.00727

Gnomad4 AMR AF: 0.0195

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.0393

Gnomad4 NFE AF: 0.0431

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0340 Hom.: 47

Bravo AF: 0.0244

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0355

EpiControl AF: 0.0373

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Autosomal recessive Robinow syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.21
Dann	Benign	0.74

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: rs41277837; hg19: chr9-94487066;