Genetic Variant TMBIM4:p.Arg230Gln (chr12-66137988-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_016056.4(TMBIM4):c.689G>A(p.Arg230Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000452 in 1,613,624 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

TMBIM4
NM_016056.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.20

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:

ENSG00000228144 (HGNC:):

ENSG00000228144 links:

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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 rank	MANE	Protein	UniProt
TMBIM4	NM_016056.4 link	c.689G>A	p.Arg230Gln	missense_variant	Exon 7 of 7	ENST00000358230.8	NP_057140.2	Q9HC24
TMBIM4	NM_001282606.2 link	c.830G>A	p.Arg277Gln	missense_variant	Exon 8 of 8		NP_001269535.1	Q9HC24G3XAA5Q9HC19
TMBIM4	NM_001282610.2 link	c.596G>A	p.Arg199Gln	missense_variant	Exon 7 of 7		NP_001269539.1	Q9HC24Q7Z782
TMBIM4	NM_001282609.2 link	c.*165G>A		3_prime_UTR_variant	Exon 7 of 7		NP_001269538.1	Q9HC24G3V1M2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMBIM4	ENST00000358230.8 link	c.689G>A	p.Arg230Gln	missense_variant	Exon 7 of 7	1	NM_016056.4	ENSP00000350965.3	Q9HC24
ENSG00000228144	ENST00000539652.1 link	n.*99G>A		non_coding_transcript_exon_variant	Exon 6 of 8	2		ENSP00000454670.1	F6UZH7
ENSG00000228144	ENST00000539652.1 link	n.*99G>A		3_prime_UTR_variant	Exon 6 of 8	2		ENSP00000454670.1	F6UZH7

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151842

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000968

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000922

AC:

AN:

249390

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135304

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1461664

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000526

AC:

AN:

151960

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000662

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.689G>A (p.R230Q) 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 689, causing the arginine (R) at amino acid position 230 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

0.21

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.094

T;.;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.50

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.3

L;.;.

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.3

D;D;D

REVEL

Benign

0.14

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.11

T;T;T

Polyphen

0.41

B;.;B

Vest4

0.57

MutPred

0.57

.;.;Loss of MoRF binding (P = 0.0214);

MVP

0.50

MPC

0.48

ClinPred

0.11

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.65

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