X-49030513-C-T

Position:

• chrX-49030513-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006521.6(TFE3):​c.1373G>A​(p.Ser458Asn) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: TFE3 NM_006521.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.368

Genes affected

TFE3 (HGNC:11752): (transcription factor binding to IGHM enhancer 3) This gene encodes a basic helix-loop-helix domain-containing transcription factor that binds MUE3-type E-box sequences in the promoter of genes. The encoded protein promotes the expression of genes downstream of transforming growth factor beta (TGF-beta) signaling. This gene may be involved in chromosomal translocations in renal cell carcinomas and other cancers, resulting in the production of fusion proteins. Translocation partners include PRCC (papillary renal cell carcinoma), NONO (non-POU domain containing, octamer-binding), and ASPSCR1 (alveolar soft part sarcoma chromosome region, candidate 1), among other genes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066957265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFE3	NM_006521.6	c.1373G>A	p.Ser458Asn	missense_variant	10/10	ENST00000315869.8	NP_006512.2
TFE3	NM_001282142.2	c.1058G>A	p.Ser353Asn	missense_variant	10/10		NP_001269071.1
TFE3	XM_024452432.2	c.*3G>A		3_prime_UTR_variant	11/11		XP_024308200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFE3	ENST00000315869.8	c.1373G>A	p.Ser458Asn	missense_variant	10/10	1	NM_006521.6	ENSP00000314129	P1
TFE3	ENST00000493583.5	c.*978G>A		3_prime_UTR_variant, NMD_transcript_variant	10/10	2		ENSP00000476976
TFE3	ENST00000495940.2			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.1373G>A (p.S458N) alteration is located in exon 10 (coding exon 10) of the TFE3 gene. This alteration results from a G to A substitution at nucleotide position 1373, causing the serine (S) at amino acid position 458 to be replaced by an asparagine (N). 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	0.094
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.039
Sift	Benign	0.27	T
Sift4G	Benign	0.61	T
Polyphen		0.0010	B
Vest4		0.074
MutPred		0.22		Loss of phosphorylation at S458 (P = 0.018);
MVP		0.13
MPC		0.11
ClinPred		0.59	D
GERP RS		2.6
Varity_R		0.22
gMVP		0.54

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: chrX-48888024;