Genetic Variant TMBIM6:p.Leu151Val (chr12-49758700-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003217.3(TMBIM6):c.451C>G(p.Leu151Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMBIM6
NM_003217.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.44

Publications

1 publications found

Variant links:

Genes affected

TMBIM6 (HGNC:11723): (transmembrane BAX inhibitor motif containing 6) Enables endoribonuclease inhibitor activity and ubiquitin protein ligase binding activity. Involved in several processes, including negative regulation of RNA metabolic process; negative regulation of intrinsic apoptotic signaling pathway; and response to L-glutamate. Acts upstream of or within negative regulation of calcium ion transport into cytosol. Located in endoplasmic reticulum membrane and mitochondrial membrane. Biomarker of cervical squamous cell carcinoma and prostate carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

TMBIM6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38619515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMBIM6	NM_003217.3 link	c.451C>G	p.Leu151Val	missense_variant	Exon 7 of 10	ENST00000267115.10	NP_003208.2	P55061-1A0A024R0Z5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMBIM6	ENST00000267115.10 link	c.451C>G	p.Leu151Val	missense_variant	Exon 7 of 10	1	NM_003217.3	ENSP00000267115.5		P55061-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251392

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.24

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

Eigen

Benign

-0.066

Eigen_PC

Benign

-0.0067

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.91

.;.;.;D;.;D;D

M_CAP

Benign

0.030

MetaRNN

Benign

0.39

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

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.2

.;M;M;.;M;M;.

PhyloP100

2.4

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.0

N;N;N;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.16

T;D;D;T;D;D;D

Sift4G

Uncertain

0.033

D;D;D;D;D;D;D

Polyphen

0.54

.;P;P;.;P;P;.

Vest4

0.34

MutPred

0.64

.;Loss of stability (P = 0.3627);Loss of stability (P = 0.3627);.;Loss of stability (P = 0.3627);Loss of stability (P = 0.3627);.;

MVP

0.58

MPC

0.67

ClinPred

0.71

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.77

Mutation Taster

=84/16

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over