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9-91722926-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_004560.4(ROR2):c.*736A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00422 in 282,858 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 13 hom., cov: 33)
Exomes 𝑓: 0.0015 ( 2 hom. )

Consequence

ROR2
NM_004560.4 3_prime_UTR

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.899
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.4).
BP6
Variant 9-91722926-T-C is Benign according to our data. Variant chr9-91722926-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 367483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00653 (995/152364) while in subpopulation AFR AF= 0.022 (915/41586). AF 95% confidence interval is 0.0208. There are 13 homozygotes in gnomad4. There are 463 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ROR2NM_004560.4 linkuse as main transcriptc.*736A>G 3_prime_UTR_variant 9/9 ENST00000375708.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ROR2ENST00000375708.4 linkuse as main transcriptc.*736A>G 3_prime_UTR_variant 9/91 NM_004560.4 P1
ROR2ENST00000375715.5 linkuse as main transcriptc.1921-346A>G intron_variant 1
ROR2ENST00000550066.5 linkuse as main transcriptn.4036A>G non_coding_transcript_exon_variant 11/112

Frequencies

GnomAD3 genomes
AF:
0.00652
AC:
993
AN:
152246
Hom.:
13
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0220
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00288
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000264
Gnomad OTH
AF:
0.00478
GnomAD4 exome
AF:
0.00152
AC:
199
AN:
130494
Hom.:
2
Cov.:
0
AF XY:
0.00141
AC XY:
94
AN XY:
66684
show subpopulations
Gnomad4 AFR exome
AF:
0.0241
Gnomad4 AMR exome
AF:
0.00170
Gnomad4 ASJ exome
AF:
0.000439
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000336
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000264
Gnomad4 OTH exome
AF:
0.00242
GnomAD4 genome
AF:
0.00653
AC:
995
AN:
152364
Hom.:
13
Cov.:
33
AF XY:
0.00621
AC XY:
463
AN XY:
74508
show subpopulations
Gnomad4 AFR
AF:
0.0220
Gnomad4 AMR
AF:
0.00288
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000265
Gnomad4 OTH
AF:
0.00473
Alfa
AF:
0.00537
Hom.:
0
Bravo
AF:
0.00767
Asia WGS
AF:
0.00173
AC:
6
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive Robinow syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Brachydactyly type B1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxJun 01, 2021See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.40
Cadd
Benign
11
Dann
Benign
0.85
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs73654047; hg19: chr9-94485208; API