chrX-49030187-T-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

TFE3 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• X-linked syndromic complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006521.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFE3	NM_006521.6	MANE Select	c.1699A>C	p.Ser567Arg	missense	Exon 10 of 10	NP_006512.2
	TFE3	NM_001282142.2		c.1384A>C	p.Ser462Arg	missense	Exon 10 of 10	NP_001269071.1	B4DIA5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFE3	ENST00000315869.8	TSL:1 MANE Select	c.1699A>C	p.Ser567Arg	missense	Exon 10 of 10	ENSP00000314129.7	P19532-1
	TFE3	ENST00000874969.1		c.1591A>C	p.Ser531Arg	missense	Exon 10 of 10	ENSP00000545028.1
	TFE3	ENST00000912302.1		c.1513A>C	p.Ser505Arg	missense	Exon 10 of 10	ENSP00000582361.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.9
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
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

hg19: chrX-48887698;