17-58308996-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004758.4(TSPOAP1):c.4276G>A(p.Glu1426Lys) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSPOAP1 NM_004758.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05

Genes affected

TSPOAP1 (HGNC:16831): (TSPO associated protein 1) Enables benzodiazepine receptor binding activity. Predicted to be involved in regulation of presynaptic cytosolic calcium ion concentration. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27550358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPOAP1	NM_004758.4	c.4276G>A	p.Glu1426Lys	missense_variant	22/32	ENST00000343736.9
TSPOAP1	NM_001261835.2	c.4276G>A	p.Glu1426Lys	missense_variant	22/32
TSPOAP1	NM_024418.3	c.4096G>A	p.Glu1366Lys	missense_variant	21/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPOAP1	ENST00000343736.9	c.4276G>A	p.Glu1426Lys	missense_variant	22/32	1	NM_004758.4	P2
TSPOAP1	ENST00000268893.10	c.4096G>A	p.Glu1366Lys	missense_variant	21/31	1		A2
TSPOAP1	ENST00000580669.6	c.1672G>A	p.Glu558Lys	missense_variant	6/16	5
TSPOAP1	ENST00000582679.1	c.421+971G>A		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 42

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

Oct 29, 2021

The c.4276G>A (p.E1426K) alteration is located in exon 22 (coding exon 22) of the TSPOAP1 gene. This alteration results from a G to A substitution at nucleotide position 4276, causing the glutamic acid (E) at amino acid position 1426 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	0.26
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.84	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.4	N;.;N
REVEL	Benign	0.084
Sift	Pathogenic	0.0	D;.;D
Sift4G	Benign	0.076	T;.;T
Polyphen		1.0	D;.;D
Vest4		0.66
MutPred		0.24		.;.;Gain of MoRF binding (P = 0.0013);
MVP		0.48
MPC		0.85
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.30
gMVP		0.72

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: chr17-56386357; COSMIC: COSV99270587; COSMIC: COSV99270587;