NM_004560.4:c.938-33C>T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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

GnomAD3 exomes AF: 0.0866 AC: 21564 AN: 248992 Hom.: 1276 AF XY: 0.0873 AC XY: 11774 AN XY: 134906

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 SAS exome AF: 0.0363

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

Gnomad4 AFR exome AF: 0.0589

Gnomad4 AMR exome AF: 0.0661

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0367

Gnomad4 FIN exome AF: 0.0830

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.103

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

Gnomad4 AFR AF: 0.0629

Gnomad4 AMR AF: 0.0931

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.000963

Gnomad4 SAS AF: 0.0313

Gnomad4 FIN AF: 0.0754

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.111

Alfa AF: 0.116 Hom.: 608

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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs10992070; hg19: chr9-94493470;