9-91725177-C-T

Variant names:

• chr9-91725177-C-T
• rs10992065
• NM_004560.4:c.1387-70G>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.1387-70G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,603,272 control chromosomes in the GnomAD database, including 66,805 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5472 hom., cov: 33)
  • Exomes 𝑓: 0.29 (61333 hom.)
• Consequence: ROR2 NM_004560.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.67
• Publications: 7 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=-0.95).
• BP6: Variant 9-91725177-C-T is Benign according to our data. Variant chr9-91725177-C-T is described in ClinVar as Benign. ClinVar VariationId is 1270146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROR2	NM_004560.4	c.1387-70G>A		intron_variant	Intron 8 of 8	ENST00000375708.4	NP_004551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROR2	ENST00000375708.4	c.1387-70G>A		intron_variant	Intron 8 of 8	1	NM_004560.4	ENSP00000364860.3
ROR2	ENST00000375715.5	c.967-70G>A		intron_variant	Intron 8 of 12	1		ENSP00000364867.1
ROR2	ENST00000550066.5	n.1855-70G>A		intron_variant	Intron 10 of 10	2

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38682 AN: 152008 Hom.: 5470 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.273

GnomAD4 exome AF: 0.287 AC: 416838 AN: 1451146 Hom.: 61333 AF XY: 0.288 AC XY: 207707 AN XY: 722308

African (AFR) AF: 0.123 AC: 4132 AN: 33470

American (AMR) AF: 0.368 AC: 16441 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 7894 AN: 26136

East Asian (EAS) AF: 0.356 AC: 14132 AN: 39692

South Asian (SAS) AF: 0.301 AC: 25952 AN: 86078

European-Finnish (FIN) AF: 0.352 AC: 15255 AN: 43286

Middle Eastern (MID) AF: 0.292 AC: 1678 AN: 5756

European-Non Finnish (NFE) AF: 0.283 AC: 314372 AN: 1111692

Other (OTH) AF: 0.282 AC: 16982 AN: 60318

GnomAD4 genome AF: 0.254 AC: 38673 AN: 152126 Hom.: 5472 Cov.: 33 AF XY: 0.260 AC XY: 19314 AN XY: 74370

African (AFR) AF: 0.132 AC: 5487 AN: 41530

American (AMR) AF: 0.314 AC: 4798 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1051 AN: 3468

East Asian (EAS) AF: 0.369 AC: 1900 AN: 5156

South Asian (SAS) AF: 0.297 AC: 1431 AN: 4824

European-Finnish (FIN) AF: 0.357 AC: 3780 AN: 10574

Middle Eastern (MID) AF: 0.271 AC: 79 AN: 292

European-Non Finnish (NFE) AF: 0.284 AC: 19328 AN: 67970

Other (OTH) AF: 0.270 AC: 571 AN: 2112

Alfa AF: 0.264 Hom.: 6682

Bravo AF: 0.248

Asia WGS AF: 0.303 AC: 1052 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Oct 16, 2018

GeneDx

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	-0.95
CADD	Benign	0.0030
DANN	Benign	0.82
PhyloP100		-3.7
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: rs10992065; hg19: chr9-94487459; COSMIC: COSV65216589;