12-66137974-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016056.4(TMBIM4):​c.703G>A​(p.Val235Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TMBIM4
NM_016056.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.766
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.08358863).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMBIM4NM_016056.4 linkc.703G>A p.Val235Ile missense_variant Exon 7 of 7 ENST00000358230.8 NP_057140.2 Q9HC24
TMBIM4NM_001282606.2 linkc.844G>A p.Val282Ile missense_variant Exon 8 of 8 NP_001269535.1 Q9HC24G3XAA5Q9HC19
TMBIM4NM_001282610.2 linkc.610G>A p.Val204Ile missense_variant Exon 7 of 7 NP_001269539.1 Q9HC24Q7Z782
TMBIM4NM_001282609.2 linkc.*179G>A 3_prime_UTR_variant Exon 7 of 7 NP_001269538.1 Q9HC24G3V1M2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMBIM4ENST00000358230.8 linkc.703G>A p.Val235Ile missense_variant Exon 7 of 7 1 NM_016056.4 ENSP00000350965.3 Q9HC24
ENSG00000228144ENST00000539652.1 linkn.*113G>A non_coding_transcript_exon_variant Exon 6 of 8 2 ENSP00000454670.1 F6UZH7
ENSG00000228144ENST00000539652.1 linkn.*113G>A 3_prime_UTR_variant Exon 6 of 8 2 ENSP00000454670.1 F6UZH7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460538
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
726446
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:
0.0000166
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 06, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.703G>A (p.V235I) alteration is located in exon 7 (coding exon 7) of the TMBIM4 gene. This alteration results from a G to A substitution at nucleotide position 703, causing the valine (V) at amino acid position 235 to be replaced by an isoleucine (I). 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
0.084
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
16
DANN
Benign
0.92
DEOGEN2
Benign
0.0059
T;.;.
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.074
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.75
T;T;T
M_CAP
Benign
0.0084
T
MetaRNN
Benign
0.084
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.16
N;.;.
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-0.14
N;N;N
REVEL
Benign
0.057
Sift
Benign
0.48
T;T;T
Sift4G
Benign
0.50
T;T;T
Polyphen
0.042
B;.;B
Vest4
0.030
MutPred
0.30
.;.;Gain of methylation at K285 (P = 0.0542);
MVP
0.54
MPC
0.19
ClinPred
0.33
T
GERP RS
3.9
Varity_R
0.042
gMVP
0.084

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs530605444; hg19: chr12-66531754; API