2-218280090-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022152.6(TMBIM1):c.239T>C(p.Val80Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TMBIM1 NM_022152.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.297

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]

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]

MIR6513 (HGNC:50247): (microRNA 6513) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

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=0.03732738).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMBIM1	NM_022152.6	c.239T>C	p.Val80Ala	missense_variant	3/12	ENST00000258412.8
PNKD	NM_015488.5	c.236+8541A>G		intron_variant		ENST00000273077.9
MIR6513	NR_106768.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMBIM1	ENST00000258412.8	c.239T>C	p.Val80Ala	missense_variant	3/12	1	NM_022152.6	P1
PNKD	ENST00000273077.9	c.236+8541A>G		intron_variant		1	NM_015488.5
MIR6513	ENST00000621188.1			downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

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

Jan 30, 2024

The c.239T>C (p.V80A) alteration is located in exon 3 (coding exon 2) of the TMBIM1 gene. This alteration results from a T to C substitution at nucleotide position 239, causing the valine (V) at amino acid position 80 to be replaced by an alanine (A). 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	0.075
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	6.6
Dann	Benign	0.92
DEOGEN2	Benign	0.0024	T;T;T;.;.;.;T;T;T;T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.23	N
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.037	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.49	N;N;N;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.58	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.055
Sift	Benign	0.72	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.68	T;T;T;T;.;.;.;.;.;T;T
Polyphen		0.0	B;B;B;.;.;.;.;.;.;.;.
Vest4		0.051
MutPred		0.33		Loss of stability (P = 0.0506);Loss of stability (P = 0.0506);Loss of stability (P = 0.0506);Loss of stability (P = 0.0506);Loss of stability (P = 0.0506);Loss of stability (P = 0.0506);Loss of stability (P = 0.0506);Loss of stability (P = 0.0506);Loss of stability (P = 0.0506);Loss of stability (P = 0.0506);Loss of stability (P = 0.0506);
MVP		0.20
MPC		0.17
ClinPred		0.091	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
gMVP		0.40

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: chr2-219144813;