4-122741906-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152618.3(BBS12):​c.14G>T​(p.Cys5Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BBS12
NM_152618.3 missense

Scores

19

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 1.70
Variant links:
Genes affected
BBS12 (HGNC:26648): (Bardet-Biedl syndrome 12) The protein encoded by this gene is part of a complex that is involved in membrane trafficking. The encoded protein is a molecular chaperone that aids in protein folding upon ATP hydrolysis. This protein also plays a role in adipocyte differentiation. Defects in this gene are a cause of Bardet-Biedl syndrome type 12. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, May 2010]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06695199).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BBS12NM_152618.3 linkuse as main transcriptc.14G>T p.Cys5Phe missense_variant 2/2 ENST00000314218.8 NP_689831.2
BBS12NM_001178007.2 linkuse as main transcriptc.14G>T p.Cys5Phe missense_variant 3/3 NP_001171478.1
BBS12XM_011531680.3 linkuse as main transcriptc.14G>T p.Cys5Phe missense_variant 2/2 XP_011529982.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BBS12ENST00000314218.8 linkuse as main transcriptc.14G>T p.Cys5Phe missense_variant 2/21 NM_152618.3 ENSP00000319062 P1
BBS12ENST00000542236.5 linkuse as main transcriptc.14G>T p.Cys5Phe missense_variant 3/32 ENSP00000438273 P1
BBS12ENST00000433287.1 linkuse as main transcriptc.14G>T p.Cys5Phe missense_variant 3/32 ENSP00000398912

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461782
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727188
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

BBS12-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 07, 2024The BBS12 c.14G>T variant is predicted to result in the amino acid substitution p.Cys5Phe. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.084
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
4.2
DANN
Benign
0.63
DEOGEN2
Benign
0.028
T;T;.
Eigen
Benign
-0.91
Eigen_PC
Benign
-0.77
FATHMM_MKL
Benign
0.60
D
LIST_S2
Benign
0.37
T;.;T
M_CAP
Benign
0.0089
T
MetaRNN
Benign
0.067
T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.2
L;L;.
MutationTaster
Benign
0.55
N;N
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.26
N;N;N
REVEL
Benign
0.042
Sift
Benign
1.0
T;T;T
Sift4G
Benign
1.0
T;T;T
Polyphen
0.0050
B;B;.
Vest4
0.10
MutPred
0.35
Loss of catalytic residue at M3 (P = 0.0318);Loss of catalytic residue at M3 (P = 0.0318);Loss of catalytic residue at M3 (P = 0.0318);
MVP
0.43
MPC
0.13
ClinPred
0.077
T
GERP RS
-0.56
Varity_R
0.055
gMVP
0.17

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-123663061; API