X-49030187-T-G

Variant names:

• chrX-49030187-T-G
• NM_006521.6:c.1699A>C

Variant summary

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

The NM_006521.6(TFE3):​c.1699A>C​(p.Ser567Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: TFE3 NM_006521.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFE3	NM_006521.6	c.1699A>C	p.Ser567Arg	missense_variant	Exon 10 of 10	ENST00000315869.8	NP_006512.2
TFE3	NM_001282142.2	c.1384A>C	p.Ser462Arg	missense_variant	Exon 10 of 10		NP_001269071.1
TFE3	XM_024452432.2	c.*329A>C		3_prime_UTR_variant	Exon 11 of 11		XP_024308200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFE3	ENST00000315869.8	c.1699A>C	p.Ser567Arg	missense_variant	Exon 10 of 10	1	NM_006521.6	ENSP00000314129.7
TFE3	ENST00000493583.5	n.*1304A>C		non_coding_transcript_exon_variant	Exon 10 of 10	2		ENSP00000476976.1
TFE3	ENST00000493583.5	n.*1304A>C		3_prime_UTR_variant	Exon 10 of 10	2		ENSP00000476976.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 16, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	-0.014	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.49		Loss of phosphorylation at S567 (P = 5e-04);
MVP		0.63
MPC		0.15
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.84
gMVP		0.70

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-48887698;