17-1295596-A-T

Variant names:

• chr17-1295596-A-T
• rs762625401
• NM_172367.3:c.493A>T

Variant summary

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

The NM_172367.3(TRARG1):​c.493A>T​(p.Met165Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M165I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRARG1 NM_172367.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.625

Genes affected

TRARG1 (HGNC:29592): (trafficking regulator of GLUT4 (SLC2A4) 1) Predicted to be involved in endosome to plasma membrane protein transport and glucose import in response to insulin stimulus. Predicted to act upstream of or within vesicle fusion to plasma membrane. Predicted to be located in cytoplasmic vesicle membrane and plasma membrane. Predicted to be active in membrane. [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=0.08982724).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRARG1	NM_172367.3	c.493A>T	p.Met165Leu	missense_variant	Exon 2 of 3	ENST00000333813.4	NP_758955.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRARG1	ENST00000333813.4	c.493A>T	p.Met165Leu	missense_variant	Exon 2 of 3	1	NM_172367.3	ENSP00000329548.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460444 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726590

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 15, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.493A>T (p.M165L) alteration is located in exon 2 (coding exon 2) of the TUSC5 gene. This alteration results from a A to T substitution at nucleotide position 493, causing the methionine (M) at amino acid position 165 to be replaced by a leucine (L). 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	0.099
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	5.4
DANN	Benign	0.61
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.87	T
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.19
Sift	Benign	0.29	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.34
MutPred		0.55		Gain of catalytic residue at M165 (P = 0.0243);
MVP		0.16
MPC		0.047
ClinPred		0.079	T
GERP RS		1.9
Varity_R		0.069
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

LitVar

Other links and lift over

dbSNP: rs762625401; hg19: chr17-1198890;