12-66147932-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_016056.4(TMBIM4):c.322G>A(p.Glu108Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000621 in 1,611,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
TMBIM4
NM_016056.4 missense
NM_016056.4 missense
Scores
4
12
3
Clinical Significance
Conservation
PhyloP100: 5.64
Genes affected
TMBIM4 (HGNC:24257): (transmembrane BAX inhibitor motif containing 4) Involved in negative regulation of apoptotic process and regulation of calcium-mediated signaling. Located in Golgi stack. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.798
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMBIM4 | NM_016056.4 | c.322G>A | p.Glu108Lys | missense_variant | 4/7 | ENST00000358230.8 | NP_057140.2 | |
TMBIM4 | NM_001282606.2 | c.463G>A | p.Glu155Lys | missense_variant | 5/8 | NP_001269535.1 | ||
TMBIM4 | NM_001282610.2 | c.229G>A | p.Glu77Lys | missense_variant | 4/7 | NP_001269539.1 | ||
TMBIM4 | NM_001282609.2 | c.322G>A | p.Glu108Lys | missense_variant | 4/7 | NP_001269538.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TMBIM4 | ENST00000358230.8 | c.322G>A | p.Glu108Lys | missense_variant | 4/7 | 1 | NM_016056.4 | ENSP00000350965 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000406 AC: 1AN: 246604Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133850
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GnomAD4 exome AF: 0.00000480 AC: 7AN: 1459216Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3AN XY: 725868
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74332
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 30, 2022 | The c.322G>A (p.E108K) alteration is located in exon 4 (coding exon 4) of the TMBIM4 gene. This alteration results from a G to A substitution at nucleotide position 322, causing the glutamic acid (E) at amino acid position 108 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;D;.;D
REVEL
Uncertain
Sift
Benign
D;.;D;D;.;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
D;.;D;D;.;.
Vest4
MutPred
0.55
.;.;.;Gain of ubiquitination at E155 (P = 0.0121);.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at