NM_004560.4:c.937+10C>T

Variant names:

• chr9-91733112-G-A
• rs201083970
• NM_004560.4:c.937+10C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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=-0.74).
• BP6: Variant 9-91733112-G-A is Benign according to our data. Variant chr9-91733112-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004560.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR2	NM_004560.4	MANE Select	c.937+10C>T		intron	N/A	NP_004551.2
	ROR2	NM_001318204.2		c.937+10C>T		intron	N/A	NP_001305133.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR2	ENST00000375708.4	TSL:1 MANE Select	c.937+10C>T		intron	N/A	ENSP00000364860.3
	ROR2	ENST00000375715.5	TSL:1	c.517+10C>T		intron	N/A	ENSP00000364867.1
	ROR2	ENST00000964760.1		c.856+91C>T		intron	N/A	ENSP00000634819.1

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

GnomAD2 exomes AF: 0.00304 AC: 596 AN: 196148 AF XY: 0.00337

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 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

African (AFR) AF: 0.000543 AC: 18 AN: 33130

American (AMR) AF: 0.00177 AC: 72 AN: 40578

Ashkenazi Jewish (ASJ) AF: 0.00463 AC: 118 AN: 25498

East Asian (EAS) AF: 0.000155 AC: 6 AN: 38660

South Asian (SAS) AF: 0.00276 AC: 229 AN: 82924

European-Finnish (FIN) AF: 0.00404 AC: 191 AN: 47326

Middle Eastern (MID) AF: 0.00152 AC: 8 AN: 5260

European-Non Finnish (NFE) AF: 0.00506 AC: 5568 AN: 1100166

Other (OTH) AF: 0.00381 AC: 226 AN: 59324

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

African (AFR) AF: 0.000891 AC: 37 AN: 41514

American (AMR) AF: 0.00209 AC: 32 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3466

East Asian (EAS) AF: 0.000586 AC: 3 AN: 5122

South Asian (SAS) AF: 0.00229 AC: 11 AN: 4814

European-Finnish (FIN) AF: 0.00556 AC: 59 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00437 AC: 297 AN: 67976

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00369 Hom.: 0

Bravo AF: 0.00289

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Autosomal recessive Robinow syndrome (1)
-	-	1	Brachydactyly type B1 (1)
-	-	1	Brachydactyly type B1;C5399974:Autosomal recessive Robinow syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.69
DANN	Benign	0.86
PhyloP100		0.011
Mutation Taster		=100/0	polymorphism

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