2-218280111-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_022152.6(TMBIM1):c.218A>G(p.Tyr73Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
TMBIM1
NM_022152.6 missense
NM_022152.6 missense
Scores
1
5
12
Clinical Significance
Conservation
PhyloP100: 2.14
Genes affected
TMBIM1 (HGNC:23410): (transmembrane BAX inhibitor motif containing 1) Enables death receptor binding activity. Involved in negative regulation of Fas signaling pathway; negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; and negative regulation of protein localization to plasma membrane. Located in Golgi apparatus; endosome membrane; and lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]
PNKD (HGNC:9153): (PNKD metallo-beta-lactamase domain containing) This gene is thought to play a role in the regulation of myofibrillogenesis. Mutations in this gene have been associated with the movement disorder paroxysmal non-kinesigenic dyskinesia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]
MIR6513 (HGNC:50247): (microRNA 6513) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.2920646).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMBIM1 | NM_022152.6 | c.218A>G | p.Tyr73Cys | missense_variant | 3/12 | ENST00000258412.8 | |
PNKD | NM_015488.5 | c.236+8562T>C | intron_variant | ENST00000273077.9 | |||
MIR6513 | NR_106768.1 | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMBIM1 | ENST00000258412.8 | c.218A>G | p.Tyr73Cys | missense_variant | 3/12 | 1 | NM_022152.6 | P1 | |
PNKD | ENST00000273077.9 | c.236+8562T>C | intron_variant | 1 | NM_015488.5 | ||||
MIR6513 | ENST00000621188.1 | downstream_gene_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152240Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251400Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135878
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461650Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727170
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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 | May 18, 2022 | The c.218A>G (p.Y73C) alteration is located in exon 3 (coding exon 2) of the TMBIM1 gene. This alteration results from a A to G substitution at nucleotide position 218, causing the tyrosine (Y) at amino acid position 73 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;T;T;.;.;.;T;T;T;T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;D;D;D;D;D;D;D;D;D
REVEL
Benign
Sift
Benign
T;T;T;D;D;D;D;D;D;D;D;D
Sift4G
Benign
T;T;T;T;.;.;.;.;.;D;D;D
Polyphen
P;P;P;.;.;.;.;.;.;.;.;.
Vest4
MutPred
Loss of phosphorylation at Y73 (P = 0.0041);Loss of phosphorylation at Y73 (P = 0.0041);Loss of phosphorylation at Y73 (P = 0.0041);Loss of phosphorylation at Y73 (P = 0.0041);Loss of phosphorylation at Y73 (P = 0.0041);Loss of phosphorylation at Y73 (P = 0.0041);Loss of phosphorylation at Y73 (P = 0.0041);Loss of phosphorylation at Y73 (P = 0.0041);Loss of phosphorylation at Y73 (P = 0.0041);Loss of phosphorylation at Y73 (P = 0.0041);Loss of phosphorylation at Y73 (P = 0.0041);Loss of phosphorylation at Y73 (P = 0.0041);
MVP
MPC
0.43
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