9-91723646-C-T

Variant names:

• chr9-91723646-C-T
• rs2230578
• NM_004560.4:c.*16G>A

Variant summary

Our verdict is Benign. The variant received -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:8
• Conservation: PhyloP100: -3.29
• Publications: 15 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)
• autosomal recessive Robinow syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 199097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.905 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROR2	NM_004560.4	c.*16G>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000375708.4	NP_004551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROR2	ENST00000375708.4	c.*16G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_004560.4	ENSP00000364860.3
ROR2	ENST00000375715.5	c.1920+508G>A		intron_variant	Intron 9 of 12	1		ENSP00000364867.1
ROR2	ENST00000550066.5	n.3316G>A		non_coding_transcript_exon_variant	Exon 11 of 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

GnomAD2 exomes AF: 0.735 AC: 182694 AN: 248436 AF XY: 0.723

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 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

African (AFR) AF: 0.769 AC: 25725 AN: 33470

American (AMR) AF: 0.846 AC: 37788 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.637 AC: 16615 AN: 26066

East Asian (EAS) AF: 0.946 AC: 37548 AN: 39698

South Asian (SAS) AF: 0.630 AC: 54284 AN: 86142

European-Finnish (FIN) AF: 0.776 AC: 40872 AN: 52644

Middle Eastern (MID) AF: 0.669 AC: 3589 AN: 5366

European-Non Finnish (NFE) AF: 0.690 AC: 767107 AN: 1111292

Other (OTH) AF: 0.704 AC: 42445 AN: 60288

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

African (AFR) AF: 0.759 AC: 31472 AN: 41458

American (AMR) AF: 0.775 AC: 11848 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 2183 AN: 3468

East Asian (EAS) AF: 0.927 AC: 4763 AN: 5140

South Asian (SAS) AF: 0.623 AC: 2996 AN: 4812

European-Finnish (FIN) AF: 0.794 AC: 8417 AN: 10598

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.691 AC: 46982 AN: 67948

Other (OTH) AF: 0.716 AC: 1513 AN: 2112

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Apr 13, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive Robinow syndrome Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brachydactyly type B1 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Oct 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.15
DANN	Benign	0.56
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism (auto)

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