2-218279302-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022152.6(TMBIM1):c.355A>G(p.Ile119Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000906 in 1,435,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000091 ( 0 hom. )

Consequence

TMBIM1
NM_022152.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.362

Variant links:

Genes affected

TMBIM1 (HGNC:23410): (transmembrane BAX inhibitor motif containing 1) Enables death receptor binding activity. Involved in negative regulation of Fas signaling pathway; negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; and negative regulation of protein localization to plasma membrane. Located in Golgi apparatus; endosome membrane; and lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMBIM1 links:

PNKD (HGNC:9153): (PNKD metallo-beta-lactamase domain containing) This gene is thought to play a role in the regulation of myofibrillogenesis. Mutations in this gene have been associated with the movement disorder paroxysmal non-kinesigenic dyskinesia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

PNKD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05987534).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMBIM1	NM_022152.6 linkuse as main transcript	c.355A>G	p.Ile119Val	missense_variant	4/12	ENST00000258412.8
PNKD	NM_015488.5 linkuse as main transcript	c.236+7753T>C		intron_variant		ENST00000273077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMBIM1	ENST00000258412.8 linkuse as main transcript	c.355A>G	p.Ile119Val	missense_variant	4/12	1	NM_022152.6	P1
PNKD	ENST00000273077.9 linkuse as main transcript	c.236+7753T>C		intron_variant		1	NM_015488.5		Q8N490-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000875

AC:

AN:

228474

Hom.:

AF XY:

0.00000812

AC XY:

AN XY:

123108

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:

0.0000192

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000906

AC:

AN:

1435004

Hom.:

Cov.:

AF XY:

0.00000843

AC XY:

AN XY:

711902

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000413

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000243

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000455

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

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

Aug 28, 2023

The c.355A>G (p.I119V) alteration is located in exon 4 (coding exon 3) of the TMBIM1 gene. This alteration results from a A to G substitution at nucleotide position 355, causing the isoleucine (I) at amino acid position 119 to be replaced by a valine (V). 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

0.054

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.64

Cadd

Benign

0.59

Dann

Benign

0.83

DEOGEN2

Benign

0.0044

T;T;T;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.12

M_CAP

Benign

0.0039

MetaRNN

Benign

0.060

T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.055

N;N;N;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.38

N;N;N;N;N;N

REVEL

Benign

0.053

Sift

Benign

0.94

T;T;T;T;T;T

Sift4G

Benign

0.58

T;T;T;T;.;.

Polyphen

0.0

B;B;B;.;.;.

Vest4

0.17

MutPred

0.62

Loss of stability (P = 0.1334);Loss of stability (P = 0.1334);Loss of stability (P = 0.1334);Loss of stability (P = 0.1334);Loss of stability (P = 0.1334);Loss of stability (P = 0.1334);

MVP

0.27

MPC

0.12

ClinPred

0.027

GERP RS

-0.0044

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.022

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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