rs148340413

Positions:

• chr9-91733329-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004560.4(ROR2):​c.730C>T​(p.Arg244Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000376 in 1,612,308 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R244P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00043 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (6 hom.)
• Consequence: ROR2 NM_004560.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.315

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01230076).
• BP6: Variant 9-91733329-G-A is Benign according to our data. Variant chr9-91733329-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198176.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=2}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00037 (540/1459952) while in subpopulation SAS AF= 0.00439 (378/86118). AF 95% confidence interval is 0.00402. There are 6 homozygotes in gnomad4_exome. There are 351 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROR2	NM_004560.4	c.730C>T	p.Arg244Trp	missense_variant	6/9	ENST00000375708.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROR2	ENST00000375708.4	c.730C>T	p.Arg244Trp	missense_variant	6/9	1	NM_004560.4	P1
ROR2	ENST00000375715.5	c.310C>T	p.Arg104Trp	missense_variant	6/13	1
ROR2	ENST00000550066.5	n.1198C>T		non_coding_transcript_exon_variant	8/11	2

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152238 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000668 AC: 165 AN: 247100 Hom.: 2 AF XY: 0.000864 AC XY: 116 AN XY: 134274

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.00420

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000540

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000370 AC: 540 AN: 1459952 Hom.: 6 Cov.: 35 AF XY: 0.000483 AC XY: 351 AN XY: 726324

Gnomad4 AFR exome AF: 0.000837

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000920

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00439

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000630

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152356 Hom.: 1 Cov.: 33 AF XY: 0.000550 AC XY: 41 AN XY: 74502

Gnomad4 AFR AF: 0.000769

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000191 Hom.: 0

Bravo AF: 0.000438

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000701 AC: 85

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive Robinow syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The ROR2 c.730C>T (p.Arg244Trp) variant has been reported in one patient in a homozygous state (Ali et al. 2007). The variant was absent from 50 ethnically matched controls but is reported at a frequency of 0.00409 in the South Asian population in the 1000 Genomes Project. Functional studies using transfected HeLa cells demonstrated that the variant protein localized to the endoplasmic reticulum while the wild type protein localized in the plasma membrane (Ali et al. 2007). Based on the evidence, the p.Arg244Trp variant is classified as a variant of unknown significance but suspicious for pathogenicity for Robinow syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 29, 2019	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	ROR2: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 15, 2022	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 21, 2018

- -

Brachydactyly type B1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T;D
Eigen	Benign	0.12
Eigen_PC	Benign	0.020
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Uncertain	0.0050	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		1.0	D;D
Vest4		0.61
MVP		0.86
MPC		0.70
ClinPred		0.053	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.29
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148340413; hg19: chr9-94495611; COSMIC: COSV65218728;