chr9-91757363-G-A

Variant names:

• chr9-91757363-G-A
• rs145568368
• NM_004560.4:c.372C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004560.4(ROR2):​c.372C>T​(p.Asp124Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00361 in 1,613,978 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0037 (24 hom.)
• Consequence: ROR2 NM_004560.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.199
• Publications: 2 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), PanelApp Australia
• autosomal recessive Robinow syndrome

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 9-91757363-G-A is Benign according to our data. Variant chr9-91757363-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.199 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00239 (363/152084) while in subpopulation NFE AF = 0.00409 (278/67998). AF 95% confidence interval is 0.00369. There are 2 homozygotes in GnomAd4. There are 166 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.372C>T	p.Asp124Asp	synonymous	Exon 3 of 9	NP_004551.2
	ROR2	NM_001318204.2		c.372C>T	p.Asp124Asp	synonymous	Exon 3 of 8	NP_001305133.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR2	ENST00000375708.4	TSL:1 MANE Select	c.372C>T	p.Asp124Asp	synonymous	Exon 3 of 9	ENSP00000364860.3	Q01974
	ROR2	ENST00000375715.5	TSL:1	c.-49C>T		5_prime_UTR	Exon 3 of 13	ENSP00000364867.1	B1APY4
	ROR2	ENST00000964760.1		c.372C>T	p.Asp124Asp	synonymous	Exon 3 of 9	ENSP00000634819.1

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 363 AN: 151966 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000846

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00333

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00409

Gnomad OTH AF: 0.00145

GnomAD2 exomes AF: 0.00269 AC: 676 AN: 251490 AF XY: 0.00302

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00385

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00374 AC: 5469 AN: 1461894 Hom.: 24 Cov.: 32 AF XY: 0.00379 AC XY: 2759 AN XY: 727248

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.00179 AC: 80 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00478 AC: 412 AN: 86258

European-Finnish (FIN) AF: 0.000393 AC: 21 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00426 AC: 4737 AN: 1112012

Other (OTH) AF: 0.00306 AC: 185 AN: 60396

GnomAD4 genome AF: 0.00239 AC: 363 AN: 152084 Hom.: 2 Cov.: 31 AF XY: 0.00223 AC XY: 166 AN XY: 74334

African (AFR) AF: 0.000843 AC: 35 AN: 41508

American (AMR) AF: 0.00157 AC: 24 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00334 AC: 16 AN: 4794

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00409 AC: 278 AN: 67998

Other (OTH) AF: 0.00143 AC: 3 AN: 2098

Alfa AF: 0.00293 Hom.: 1

Bravo AF: 0.00254

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00480

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	5.7
DANN	Benign	0.71
PhyloP100		0.20
Mutation Taster		=295/5	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: rs145568368; hg19: chr9-94519645;