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9-91723433-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004560.4(ROR2):c.*229C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 610,726 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 31 hom., cov: 32)
Exomes 𝑓: 0.0015 ( 15 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: -0.275
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 9-91723433-G-A is Benign according to our data. Variant chr9-91723433-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 367491.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 = 0.0117 (1781/152300) while in subpopulation AFR AF= 0.0405 (1685/41556). AF 95% confidence interval is 0.0389. There are 31 homozygotes in gnomad4. There are 874 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
High Homozygotes in GnomAd at 31 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ROR2NM_004560.4 linkuse as main transcriptc.*229C>T 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.*229C>T 3_prime_UTR_variant 9/91 NM_004560.4 P1
ROR2ENST00000375715.5 linkuse as main transcriptc.1920+721C>T intron_variant 1
ROR2ENST00000550066.5 linkuse as main transcriptn.3529C>T non_coding_transcript_exon_variant 11/112

Frequencies

GnomAD3 genomes
AF:
0.0117
AC:
1778
AN:
152182
Hom.:
31
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0406
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00510
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00813
GnomAD4 exome
AF:
0.00154
AC:
704
AN:
458426
Hom.:
15
Cov.:
5
AF XY:
0.00123
AC XY:
296
AN XY:
239996
show subpopulations
Gnomad4 AFR exome
AF:
0.0429
Gnomad4 AMR exome
AF:
0.00312
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000900
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000638
Gnomad4 OTH exome
AF:
0.00307
GnomAD4 genome
AF:
0.0117
AC:
1781
AN:
152300
Hom.:
31
Cov.:
32
AF XY:
0.0117
AC XY:
874
AN XY:
74466
show subpopulations
Gnomad4 AFR
AF:
0.0405
Gnomad4 AMR
AF:
0.00510
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00804
Alfa
AF:
0.00832
Hom.:
4
Bravo
AF:
0.0131
Asia WGS
AF:
0.00404
AC:
14
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 testingGeneDxNov 16, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
Cadd
Benign
1.4
Dann
Benign
0.40

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: rs75004227; hg19: chr9-94485715; API