rs201083970

chr9-91733112-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004560.4(ROR2):c.937+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,584,986 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (24 hom.)
• Consequence: ROR2 NM_004560.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0110

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=-0.74).
• BP6: Variant 9-91733112-G-A is Benign according to our data. Variant chr9-91733112-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 198175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00306 (466/152120) while in subpopulation NFE AF= 0.00437 (297/67976). AF 95% confidence interval is 0.00396. There are 3 homozygotes in gnomad4. There are 239 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROR2	NM_004560.4	c.937+10C>T		intron_variant		ENST00000375708.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROR2	ENST00000375708.4	c.937+10C>T		intron_variant		1	NM_004560.4	P1
ROR2	ENST00000375715.5	c.517+10C>T		intron_variant		1
ROR2	ENST00000550066.5	n.1405+10C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00307 AC: 467 AN: 152000 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.000779

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00556

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00437

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00304 AC: 596 AN: 196148 Hom.: 3 AF XY: 0.00337 AC XY: 363 AN XY: 107796

Gnomad AFR exome AF: 0.000662

Gnomad AMR exome AF: 0.00178

Gnomad ASJ exome AF: 0.00527

Gnomad EAS exome AF: 0.000263

Gnomad SAS exome AF: 0.00299

Gnomad FIN exome AF: 0.00448

Gnomad NFE exome AF: 0.00373

Gnomad OTH exome AF: 0.00411

GnomAD4 exome AF: 0.00449 AC: 6436 AN: 1432866 Hom.: 24 Cov.: 31 AF XY: 0.00443 AC XY: 3147 AN XY: 710438

Gnomad4 AFR exome AF: 0.000543

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.00463

Gnomad4 EAS exome AF: 0.000155

Gnomad4 SAS exome AF: 0.00276

Gnomad4 FIN exome AF: 0.00404

Gnomad4 NFE exome AF: 0.00506

Gnomad4 OTH exome AF: 0.00381

GnomAD4 genome AF: 0.00306 AC: 466 AN: 152120 Hom.: 3 Cov.: 33 AF XY: 0.00321 AC XY: 239 AN XY: 74384

Gnomad4 AFR AF: 0.000891

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.000586

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.00556

Gnomad4 NFE AF: 0.00437

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00369 Hom.: 0

Bravo AF: 0.00289

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 04, 2015	- -

Autosomal recessive Robinow syndrome Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Brachydactyly type B1;C5399974:Autosomal recessive Robinow syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 23, 2021

- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.69
Dann	Benign	0.86

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: rs201083970; hg19: chr9-94495394; COSMIC: COSV100996178;