12-49758239-G-T

Position:

• chr12-49758239-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000267115.10(TMBIM6):​c.299G>T​(p.Gly100Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMBIM6 ENST00000267115.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.52

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMBIM6	NM_003217.3	c.299G>T	p.Gly100Val	missense_variant	5/10	ENST00000267115.10	NP_003208.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMBIM6	ENST00000267115.10	c.299G>T	p.Gly100Val	missense_variant	5/10	1	NM_003217.3	ENSP00000267115	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.473G>T (p.G158V) alteration is located in exon 5 (coding exon 5) of the TMBIM6 gene. This alteration results from a G to T substitution at nucleotide position 473, causing the glycine (G) at amino acid position 158 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	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;T;.;T;T;T;.;T;T;T;T
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	.;D;D;.;.;.;D;D;D;.;D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.4	.;.;.;.;M;M;.;.;.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-8.6	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;D;.;.;.;D;D;.
Vest4		0.93, 0.92, 0.93
MutPred		0.85		Gain of stability (P = 0.0636);Gain of stability (P = 0.0636);Gain of stability (P = 0.0636);.;Gain of stability (P = 0.0636);Gain of stability (P = 0.0636);Gain of stability (P = 0.0636);.;Gain of stability (P = 0.0636);Gain of stability (P = 0.0636);Gain of stability (P = 0.0636);.;
MVP		0.90
MPC		1.1
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-50152022;