12-66137974-C-T

Variant names:

• chr12-66137974-C-T
• rs530605444
• NM_016056.4:c.703G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016056.4(TMBIM4):​c.703G>A​(p.Val235Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,538 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMBIM4 NM_016056.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.766

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]

ENSG00000228144 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08358863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMBIM4	NM_016056.4	c.703G>A	p.Val235Ile	missense_variant	Exon 7 of 7	ENST00000358230.8	NP_057140.2
TMBIM4	NM_001282606.2	c.844G>A	p.Val282Ile	missense_variant	Exon 8 of 8		NP_001269535.1
TMBIM4	NM_001282610.2	c.610G>A	p.Val204Ile	missense_variant	Exon 7 of 7		NP_001269539.1
TMBIM4	NM_001282609.2	c.*179G>A		3_prime_UTR_variant	Exon 7 of 7		NP_001269538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMBIM4	ENST00000358230.8	c.703G>A	p.Val235Ile	missense_variant	Exon 7 of 7	1	NM_016056.4	ENSP00000350965.3
ENSG00000228144	ENST00000539652.1	n.*113G>A		non_coding_transcript_exon_variant	Exon 6 of 8	2		ENSP00000454670.1
ENSG00000228144	ENST00000539652.1	n.*113G>A		3_prime_UTR_variant	Exon 6 of 8	2		ENSP00000454670.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460538 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726446

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.703G>A (p.V235I) alteration is located in exon 7 (coding exon 7) of the TMBIM4 gene. This alteration results from a G to A substitution at nucleotide position 703, causing the valine (V) at amino acid position 235 to be replaced by an isoleucine (I). 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	0.084
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.0059	T;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.074
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.084	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.16	N;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.14	N;N;N
REVEL	Benign	0.057
Sift	Benign	0.48	T;T;T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.042	B;.;B
Vest4		0.030
MutPred		0.30		.;.;Gain of methylation at K285 (P = 0.0542);
MVP		0.54
MPC		0.19
ClinPred		0.33	T
GERP RS		3.9
Varity_R		0.042
gMVP		0.084

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

LitVar

Other links and lift over

dbSNP: rs530605444; hg19: chr12-66531754;