12-66153364-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000544599.5(TMBIM4):​c.-350C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TMBIM4
ENST00000544599.5 5_prime_UTR_premature_start_codon_gain

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.25
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TMBIM4NM_016056.4 linkuse as main transcriptc.182C>A p.Ser61Tyr missense_variant 2/7 ENST00000358230.8 NP_057140.2 Q9HC24
TMBIM4NM_001282606.2 linkuse as main transcriptc.323C>A p.Ser108Tyr missense_variant 3/8 NP_001269535.1 Q9HC24G3XAA5Q9HC19
TMBIM4NM_001282610.2 linkuse as main transcriptc.89C>A p.Ser30Tyr missense_variant 2/7 NP_001269539.1 Q9HC24Q7Z782
TMBIM4NM_001282609.2 linkuse as main transcriptc.182C>A p.Ser61Tyr missense_variant 2/7 NP_001269538.1 Q9HC24G3V1M2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TMBIM4ENST00000358230.8 linkuse as main transcriptc.182C>A p.Ser61Tyr missense_variant 2/71 NM_016056.4 ENSP00000350965.3 Q9HC24
ENSG00000228144ENST00000539652.1 linkuse as main transcriptn.182C>A non_coding_transcript_exon_variant 2/82 ENSP00000454670.1 F6UZH7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1437832
Hom.:
0
Cov.:
27
AF XY:
0.00
AC XY:
0
AN XY:
715972
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

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 submitterclinical testingAmbry GeneticsOct 07, 2024The c.182C>A (p.S61Y) alteration is located in exon 2 (coding exon 2) of the TMBIM4 gene. This alteration results from a C to A substitution at nucleotide position 182, causing the serine (S) at amino acid position 61 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.098
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.092
T;.;.;.;.;.
Eigen
Benign
0.11
Eigen_PC
Benign
-0.056
FATHMM_MKL
Benign
0.17
N
LIST_S2
Uncertain
0.91
D;D;D;D;D;D
M_CAP
Benign
0.047
D
MetaRNN
Uncertain
0.52
D;D;D;D;D;D
MetaSVM
Benign
-0.86
T
MutationAssessor
Uncertain
2.3
M;.;.;.;.;.
PrimateAI
Benign
0.41
T
PROVEAN
Uncertain
-3.0
D;.;D;D;.;D
REVEL
Benign
0.20
Sift
Benign
0.036
D;.;D;D;.;D
Sift4G
Uncertain
0.035
D;D;T;D;T;T
Polyphen
0.85
P;.;D;D;.;.
Vest4
0.50
MutPred
0.56
.;.;.;Gain of helix (P = 0.132);.;.;
MVP
0.70
MPC
0.77
ClinPred
0.93
D
GERP RS
3.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.34
gMVP
0.38

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
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: rs747623797; hg19: chr12-66547144; API