Variant 12-66169945-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_016056.4(TMBIM4):c.7G>A(p.Asp3Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000304 in 1,497,076 control chromosomes in the GnomAD database, including 2 homozygotes. 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 0.0016 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

TMBIM4
NM_016056.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.278

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037334561).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMBIM4	NM_016056.4 linkuse as main transcript	c.7G>A	p.Asp3Asn	missense_variant	1/7	ENST00000358230.8	NP_057140.2
TMBIM4	NM_001282606.2 linkuse as main transcript	c.7G>A	p.Asp3Asn	missense_variant	1/8		NP_001269535.1
TMBIM4	NM_001282609.2 linkuse as main transcript	c.7G>A	p.Asp3Asn	missense_variant	1/7		NP_001269538.1
TMBIM4	NM_001282610.2 linkuse as main transcript	c.-49G>A		5_prime_UTR_variant	1/7		NP_001269539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMBIM4	ENST00000358230.8 linkuse as main transcript	c.7G>A	p.Asp3Asn	missense_variant	1/7	1	NM_016056.4	ENSP00000350965	P1

Frequencies

GnomAD3 genomes

AF:

0.00155

AC:

236

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00548

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.00

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000168

AC:

AN:

101092

Hom.:

AF XY:

0.0000902

AC XY:

AN XY:

55446

show subpopulations

Gnomad AFR exome

AF:

0.00411

Gnomad AMR exome

AF:

0.000232

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000155

AC:

209

AN:

1344800

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

662660

show subpopulations

Gnomad4 AFR exome

AF:

0.00547

Gnomad4 AMR exome

AF:

0.000369

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000270

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000946

Gnomad4 OTH exome

AF:

0.000540

GnomAD4 genome

AF:

0.00162

AC:

246

AN:

152276

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

131

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00570

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000813

Hom.:

Bravo

AF:

0.00184

ESP6500AA

AF:

0.00244

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000207

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

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

Aug 13, 2021

The c.7G>A (p.D3N) alteration is located in exon 1 (coding exon 1) of the TMBIM4 gene. This alteration results from a G to A substitution at nucleotide position 7, causing the aspartic acid (D) at amino acid position 3 to be replaced by an asparagine (N). 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

0.11

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.3

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0067

T;.;.;.;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.73

T;T;T;T;T;T;T

M_CAP

Benign

0.0090

MetaRNN

Benign

0.0037

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

0.040

N;.;N;N;.;N;.

REVEL

Benign

0.0070

Sift

Benign

0.23

T;.;T;T;.;T;.

Sift4G

Benign

0.27

T;T;T;T;T;T;T

Polyphen

0.021

B;.;B;B;.;.;.

Vest4

0.093

MVP

0.23

MPC

0.23

ClinPred

0.0049

GERP RS

0.38

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.057

gMVP

0.15

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.

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