3-11817304-G-T

Variant summary

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

The NM_001284401.2(TAMM41):c.596C>A(p.Thr199Lys) 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: TAMM41 NM_001284401.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

Genes affected

TAMM41 (HGNC:25187): (TAM41 mitochondrial translocator assembly and maintenance homolog) Predicted to enable phosphatidate cytidylyltransferase activity. Predicted to be involved in CDP-diacylglycerol biosynthetic process and cardiolipin biosynthetic process. Predicted to be located in mitochondrial inner membrane. Predicted to be extrinsic component of mitochondrial inner membrane. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

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=0.068195194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAMM41	NM_001284401.2	c.596C>A	p.Thr199Lys	missense_variant	5/8	ENST00000455809.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAMM41	ENST00000455809.6	c.596C>A	p.Thr199Lys	missense_variant	5/8	3	NM_001284401.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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 20, 2023

The c.596C>A (p.T199K) alteration is located in exon 5 (coding exon 5) of the TAMM41 gene. This alteration results from a C to A substitution at nucleotide position 596, causing the threonine (T) at amino acid position 199 to be replaced by a lysine (K). 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	0.086
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	15
Dann	Benign	0.94
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.068	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.10	N;N;N
REVEL	Benign	0.043
Sift	Benign	0.47	T;T;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.26
MutPred		0.35		Loss of ubiquitination at K200 (P = 0.0471);Loss of ubiquitination at K200 (P = 0.0471);Loss of ubiquitination at K200 (P = 0.0471);
MVP		0.18
MPC		0.22
ClinPred		0.14	T
GERP RS		3.1
Varity_R		0.050
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2078321155; hg19: chr3-11858778;