9-91723646-C-T

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.*16G>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 0.705 in 1,611,668 control chromosomes in the GnomAD database, including 403,778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (40802 hom., cov: 31)
  • Exomes 𝑓: 0.70 (362976 hom.)
• Consequence: ROR2 NM_004560.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.29

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=-0.92).
• BP6: Variant 9-91723646-C-T is Benign according to our data. Variant chr9-91723646-C-T is described in ClinVar as [Benign]. Clinvar id is 199097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-91723646-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.905 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROR2	NM_004560.4	c.*16G>A		3_prime_UTR_variant	9/9	ENST00000375708.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROR2	ENST00000375708.4	c.*16G>A		3_prime_UTR_variant	9/9	1	NM_004560.4	P1
ROR2	ENST00000375715.5	c.1920+508G>A		intron_variant		1
ROR2	ENST00000550066.5	n.3316G>A		non_coding_transcript_exon_variant	11/11	2

Frequencies

GnomAD3 genomes AF: 0.730 AC: 110898 AN: 151902 Hom.: 40747 Cov.: 31

Gnomad AFR AF: 0.759

Gnomad AMI AF: 0.702

Gnomad AMR AF: 0.775

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.927

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.794

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.715

GnomAD3 exomes AF: 0.735 AC: 182694 AN: 248436 Hom.: 68257 AF XY: 0.723 AC XY: 97410 AN XY: 134788

Gnomad AFR exome AF: 0.766

Gnomad AMR exome AF: 0.855

Gnomad ASJ exome AF: 0.634

Gnomad EAS exome AF: 0.926

Gnomad SAS exome AF: 0.629

Gnomad FIN exome AF: 0.788

Gnomad NFE exome AF: 0.692

Gnomad OTH exome AF: 0.716

GnomAD4 exome AF: 0.703 AC: 1025973 AN: 1459648 Hom.: 362976 Cov.: 66 AF XY: 0.700 AC XY: 507900 AN XY: 726090

Gnomad4 AFR exome AF: 0.769

Gnomad4 AMR exome AF: 0.846

Gnomad4 ASJ exome AF: 0.637

Gnomad4 EAS exome AF: 0.946

Gnomad4 SAS exome AF: 0.630

Gnomad4 FIN exome AF: 0.776

Gnomad4 NFE exome AF: 0.690

Gnomad4 OTH exome AF: 0.704

GnomAD4 genome AF: 0.730 AC: 111012 AN: 152020 Hom.: 40802 Cov.: 31 AF XY: 0.736 AC XY: 54684 AN XY: 74312

Gnomad4 AFR AF: 0.759

Gnomad4 AMR AF: 0.775

Gnomad4 ASJ AF: 0.629

Gnomad4 EAS AF: 0.927

Gnomad4 SAS AF: 0.623

Gnomad4 FIN AF: 0.794

Gnomad4 NFE AF: 0.691

Gnomad4 OTH AF: 0.716

Alfa AF: 0.701 Hom.: 6919

Bravo AF: 0.734

Asia WGS AF: 0.768 AC: 2671 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2016	- -

Autosomal recessive Robinow syndrome Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Brachydactyly type B1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.15
Dann	Benign	0.56

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: rs2230578; hg19: chr9-94485928; COSMIC: COSV65218526;