chr12-66138762-C-A

Variant names:

• chr12-66138762-C-A
• rs749507223
• NM_016056.4:c.472G>T

Variant summary

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

The NM_016056.4(TMBIM4):​c.472G>T​(p.Ala158Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000439 in 1,389,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 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: 0.000044 (0 hom.)
• Consequence: TMBIM4 NM_016056.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.505

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMBIM4	NM_016056.4	c.472G>T	p.Ala158Ser	missense_variant	Exon 6 of 7	ENST00000358230.8	NP_057140.2
TMBIM4	NM_001282606.2	c.613G>T	p.Ala205Ser	missense_variant	Exon 7 of 8		NP_001269535.1
TMBIM4	NM_001282610.2	c.379G>T	p.Ala127Ser	missense_variant	Exon 6 of 7		NP_001269539.1
TMBIM4	NM_001282609.2	c.465-28G>T		intron_variant	Intron 5 of 6		NP_001269538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMBIM4	ENST00000358230.8	c.472G>T	p.Ala158Ser	missense_variant	Exon 6 of 7	1	NM_016056.4	ENSP00000350965.3
ENSG00000228144	ENST00000539652.1	n.465-633G>T		intron_variant	Intron 5 of 7	2		ENSP00000454670.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000265 AC: 5 AN: 188954 Hom.: 0 AF XY: 0.0000190 AC XY: 2 AN XY: 105018

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: 0.0000530

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000439 AC: 61 AN: 1389858 Hom.: 0 Cov.: 28 AF XY: 0.0000420 AC XY: 29 AN XY: 691176

Gnomad4 AFR exome AF: 0.00

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: 0.0000562

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000249 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.472G>T (p.A158S) alteration is located in exon 6 (coding exon 6) of the TMBIM4 gene. This alteration results from a G to T substitution at nucleotide position 472, causing the alanine (A) at amino acid position 158 to be replaced by a serine (S). 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	0.14
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.0048	T;.;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.74	N;.;N
REVEL	Benign	0.096
Sift	Benign	0.38	T;.;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.017	B;.;B
Vest4		0.40
MVP		0.35
MPC		0.24
ClinPred		0.067	T
GERP RS		3.1
Varity_R		0.10
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.40		Position offset: -28

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs749507223; hg19: chr12-66532542;