Genetic Variant TMBIM4:p.Pro6Arg (chr12-66169935-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016056.4(TMBIM4):c.17C>G(p.Pro6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,344,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P6L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

TMBIM4
NM_016056.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.72

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16227558).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016056.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMBIM4	NM_016056.4	MANE Select	c.17C>G	p.Pro6Arg	missense	Exon 1 of 7	NP_057140.2	Q9HC24
TMBIM4	NM_001282606.2		c.17C>G	p.Pro6Arg	missense	Exon 1 of 8	NP_001269535.1	G3XAA5
TMBIM4	NM_001282609.2		c.17C>G	p.Pro6Arg	missense	Exon 1 of 7	NP_001269538.1	G3V1M2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMBIM4	ENST00000358230.8	TSL:1 MANE Select	c.17C>G	p.Pro6Arg	missense	Exon 1 of 7	ENSP00000350965.3	Q9HC24
TMBIM4	ENST00000542724.5	TSL:1	c.17C>G	p.Pro6Arg	missense	Exon 1 of 7	ENSP00000441291.2	G3V1M2
TMBIM4	ENST00000398033.8	TSL:1	c.17C>G	p.Pro6Arg	missense	Exon 1 of 6	ENSP00000381114.4	E7EWY5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000997

AC:

AN:

100272

AF XY:

0.0000182

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000149

AC:

AN:

1344080

Hom.:

Cov.:

AF XY:

0.00000302

AC XY:

AN XY:

662234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26818

American (AMR)

AF:

0.00

AC:

AN:

23958

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23156

East Asian (EAS)

AF:

0.00

AC:

AN:

29748

South Asian (SAS)

AF:

0.0000270

AC:

AN:

73962

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48672

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5538

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1056698

Other (OTH)

AF:

0.00

AC:

AN:

55530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

Eigen

Benign

-0.098

Eigen_PC

Benign

-0.035

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.79

M_CAP

Benign

0.030

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

2.7

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.3

REVEL

Benign

0.058

Sift

Benign

0.37

Sift4G

Uncertain

0.016

Polyphen

0.52

Vest4

0.16

MutPred

0.22

Gain of solvent accessibility (P = 0.0789)

MVP

0.59

MPC

0.35

ClinPred

0.40

GERP RS

4.8

PromoterAI

0.23

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.088

gMVP

0.19

Mutation Taster

=266/34

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over