rs10992070

Variant names:

• chr9-91731188-G-A
• rs10992070
• NM_004560.4:c.938-33C>T

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.938-33C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,612,854 control chromosomes in the GnomAD database, including 11,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (803 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10274 hom.)
• Consequence: ROR2 NM_004560.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.50
• Publications: 4 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=-0.91).
• BP6: Variant 9-91731188-G-A is Benign according to our data. Variant chr9-91731188-G-A is described in ClinVar as Benign. ClinVar VariationId is 259432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROR2	NM_004560.4	c.938-33C>T		intron_variant	Intron 6 of 8	ENST00000375708.4	NP_004551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROR2	ENST00000375708.4	c.938-33C>T		intron_variant	Intron 6 of 8	1	NM_004560.4	ENSP00000364860.3
ROR2	ENST00000375715.5	c.518-33C>T		intron_variant	Intron 6 of 12	1		ENSP00000364867.1
ROR2	ENST00000550066.5	n.1406-33C>T		intron_variant	Intron 8 of 10	2

Frequencies

GnomAD3 genomes AF: 0.0954 AC: 14504 AN: 152078 Hom.: 803 Cov.: 32

Gnomad AFR AF: 0.0629

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0932

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.0754

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.112

GnomAD2 exomes AF: 0.0866 AC: 21564 AN: 248992 AF XY: 0.0873

Gnomad AFR exome AF: 0.0587

Gnomad AMR exome AF: 0.0612

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.0800

Gnomad NFE exome AF: 0.125

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.112 AC: 163836 AN: 1460658 Hom.: 10274 Cov.: 32 AF XY: 0.111 AC XY: 80561 AN XY: 726696

African (AFR) AF: 0.0589 AC: 1971 AN: 33470

American (AMR) AF: 0.0661 AC: 2958 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2696 AN: 26136

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39700

South Asian (SAS) AF: 0.0367 AC: 3167 AN: 86204

European-Finnish (FIN) AF: 0.0830 AC: 4367 AN: 52622

Middle Eastern (MID) AF: 0.129 AC: 740 AN: 5758

European-Non Finnish (NFE) AF: 0.127 AC: 141714 AN: 1111680

Other (OTH) AF: 0.103 AC: 6213 AN: 60366

GnomAD4 genome AF: 0.0953 AC: 14510 AN: 152196 Hom.: 803 Cov.: 32 AF XY: 0.0903 AC XY: 6718 AN XY: 74408

African (AFR) AF: 0.0629 AC: 2612 AN: 41530

American (AMR) AF: 0.0931 AC: 1424 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 366 AN: 3472

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5192

South Asian (SAS) AF: 0.0313 AC: 151 AN: 4824

European-Finnish (FIN) AF: 0.0754 AC: 799 AN: 10596

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8859 AN: 67972

Other (OTH) AF: 0.111 AC: 235 AN: 2112

Alfa AF: 0.118 Hom.: 857

Bravo AF: 0.0953

Asia WGS AF: 0.0210 AC: 75 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.15
DANN	Benign	0.51
PhyloP100		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=6/94	disease causing

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: rs10992070; hg19: chr9-94493470;