Variant chr12-66153358-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_016056.4(TMBIM4):c.188G>A(p.Arg63Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,576,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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: 0.000012 ( 0 hom. )

Consequence

TMBIM4
NM_016056.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.33

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]

TMBIM4 links:

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=0.21163642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMBIM4	NM_016056.4 linkuse as main transcript	c.188G>A	p.Arg63Gln	missense_variant	2/7	ENST00000358230.8	NP_057140.2
TMBIM4	NM_001282606.2 linkuse as main transcript	c.329G>A	p.Arg110Gln	missense_variant	3/8		NP_001269535.1
TMBIM4	NM_001282610.2 linkuse as main transcript	c.95G>A	p.Arg32Gln	missense_variant	2/7		NP_001269539.1
TMBIM4	NM_001282609.2 linkuse as main transcript	c.188G>A	p.Arg63Gln	missense_variant	2/7		NP_001269538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMBIM4	ENST00000358230.8 linkuse as main transcript	c.188G>A	p.Arg63Gln	missense_variant	2/7	1	NM_016056.4	ENSP00000350965	P1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151812

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000127

AC:

AN:

235380

Hom.:

AF XY:

0.0000156

AC XY:

AN XY:

127954

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000273

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000119

AC:

AN:

1425074

Hom.:

Cov.:

AF XY:

0.00000845

AC XY:

AN XY:

710342

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:

0.0000611

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000110

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151812

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74122

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000828

AC:

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

Dec 19, 2023

The c.188G>A (p.R63Q) alteration is located in exon 2 (coding exon 2) of the TMBIM4 gene. This alteration results from a G to A substitution at nucleotide position 188, causing the arginine (R) at amino acid position 63 to be replaced by a glutamine (Q). 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

0.10

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

T;.;.;.;.;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.47

LIST_S2

Uncertain

0.90

D;D;D;D;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.21

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.41

N;.;.;.;.;.

MutationTaster

Benign

1.0

D;N;N;N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.55

N;.;N;N;.;N

REVEL

Benign

0.018

Sift

Benign

0.18

T;.;T;T;.;T

Sift4G

Benign

0.17

T;T;T;T;T;T

Polyphen

0.10

B;.;B;P;.;.

Vest4

0.26

MutPred

0.45

.;.;.;Gain of loop (P = 0.069);.;.;

MVP

0.41

MPC

0.28

ClinPred

0.15

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over