3-50326161-C-T

Position:

• chr3-50326161-C-T

Variant summary

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

The NM_007275.3(TUSC2):​c.293G>A​(p.Arg98His) variant causes a missense change. The variant allele was found at a frequency of 0.00000691 in 1,446,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: TUSC2 NM_007275.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.58

Genes affected

TUSC2 (HGNC:17034): (tumor suppressor 2, mitochondrial calcium regulator) Predicted to be involved in inflammatory response and regulation of mitochondrial membrane potential. Predicted to act upstream of or within several processes, including natural killer cell differentiation; neutrophil-mediated killing of gram-negative bacterium; and regulation of cytokine production. Predicted to be active 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=0.36918378).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUSC2	NM_007275.3	c.293G>A	p.Arg98His	missense_variant	3/3	ENST00000232496.5	NP_009206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUSC2	ENST00000232496.5	c.293G>A	p.Arg98His	missense_variant	3/3	1	NM_007275.3	ENSP00000232496	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000691 AC: 10 AN: 1446564 Hom.: 0 Cov.: 31 AF XY: 0.00000418 AC XY: 3 AN XY: 718026

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000724

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jan 08, 2024

The c.293G>A (p.R98H) alteration is located in exon 3 (coding exon 3) of the TUSC2 gene. This alteration results from a G to A substitution at nucleotide position 293, causing the arginine (R) at amino acid position 98 to be replaced by a histidine (H). 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	Pathogenic	0.58
BayesDel_addAF	Benign	0.0099	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.20
Sift	Benign	0.14	T
Sift4G	Benign	0.15	T
Polyphen		0.99	D
Vest4		0.23
MutPred		0.34		Loss of catalytic residue at R98 (P = 0.057);
MVP		0.23
MPC		0.78
ClinPred		0.62	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1553717365; hg19: chr3-50363592;