12-66138046-C-G

Variant names:

• chr12-66138046-C-G
• rs748307919
• NM_016056.4:c.631G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016056.4(TMBIM4):​c.631G>C​(p.Val211Leu) 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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V211I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMBIM4 NM_016056.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.50
• Publications: 4 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20491832).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016056.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMBIM4	NM_016056.4	MANE Select	c.631G>C	p.Val211Leu	missense	Exon 7 of 7	NP_057140.2	Q9HC24
	TMBIM4	NM_001282606.2		c.772G>C	p.Val258Leu	missense	Exon 8 of 8	NP_001269535.1	G3XAA5
	TMBIM4	NM_001282610.2		c.538G>C	p.Val180Leu	missense	Exon 7 of 7	NP_001269539.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMBIM4	ENST00000358230.8	TSL:1 MANE Select	c.631G>C	p.Val211Leu	missense	Exon 7 of 7	ENSP00000350965.3	Q9HC24
	TMBIM4	ENST00000544599.5	TSL:1	c.100G>C	p.Val34Leu	missense	Exon 7 of 7	ENSP00000444639.1	G3V1R8
	TMBIM4	ENST00000542724.5	TSL:1	c.*107G>C		3_prime_UTR	Exon 7 of 7	ENSP00000441291.2	G3V1M2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.5
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.17
Sift	Benign	0.052	T
Sift4G	Uncertain	0.038	D
Polyphen		0.0060	B
Vest4		0.37
MutPred		0.62		Gain of disorder (P = 0.1389)
MVP		0.50
MPC		0.27
ClinPred		0.30	T
GERP RS		3.8
Varity_R		0.11
gMVP		0.44
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs748307919; hg19: chr12-66531826;