rs748575488

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001142568.3(BBX):​c.283C>A​(p.Arg95Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R95C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BBX
NM_001142568.3 missense

Scores

16
2
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.54
Variant links:
Genes affected
BBX (HGNC:14422): (BBX high mobility group box domain containing) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within bone development. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BBXNM_001142568.3 linkc.283C>A p.Arg95Ser missense_variant Exon 5 of 18 ENST00000325805.13 NP_001136040.1 Q8WY36-1A8K6U2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BBXENST00000325805.13 linkc.283C>A p.Arg95Ser missense_variant Exon 5 of 18 1 NM_001142568.3 ENSP00000319974.8 Q8WY36-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152110
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251084
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135674
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461556
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
727070
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152110
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
.;D;D;.;.;D;T;D;.;.;.;T;.;.
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
.;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.4
M;.;M;.;M;.;.;.;.;M;.;.;.;.
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-4.7
D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.0080
D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;D;.;.;.;.;.;.;D;.;.;.;.
Vest4
0.74
MutPred
0.90
Gain of glycosylation at S96 (P = 0.0028);Gain of glycosylation at S96 (P = 0.0028);Gain of glycosylation at S96 (P = 0.0028);Gain of glycosylation at S96 (P = 0.0028);Gain of glycosylation at S96 (P = 0.0028);Gain of glycosylation at S96 (P = 0.0028);Gain of glycosylation at S96 (P = 0.0028);Gain of glycosylation at S96 (P = 0.0028);Gain of glycosylation at S96 (P = 0.0028);Gain of glycosylation at S96 (P = 0.0028);Gain of glycosylation at S96 (P = 0.0028);Gain of glycosylation at S96 (P = 0.0028);Gain of glycosylation at S96 (P = 0.0028);Gain of glycosylation at S96 (P = 0.0028);
MVP
0.97
MPC
0.69
ClinPred
1.0
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.95
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.20
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.20
Position offset: 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: rs748575488; hg19: chr3-107435574; API