rs782285732

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_006521.6(TFE3):c.1592G>A(p.Gly531Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000823 in 1,202,576 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 32 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000080 ( 0 hom. 31 hem. )

Consequence

TFE3
NM_006521.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.707

Publications

1 publications found

Variant links:

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

TFE3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12063998).

BP6

Variant X-49030294-C-T is Benign according to our data. Variant chrX-49030294-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2660498.

BS2

High AC in GnomAd4 at 12 XL,AD gene.

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.1592G>A	p.Gly531Glu	missense	Exon 10 of 10	NP_006512.2
	TFE3	NM_001282142.2		c.1277G>A	p.Gly426Glu	missense	Exon 10 of 10	NP_001269071.1	B4DIA5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TFE3	ENST00000315869.8	TSL:1 MANE Select	c.1592G>A	p.Gly531Glu	missense	Exon 10 of 10	ENSP00000314129.7	P19532-1
TFE3	ENST00000874969.1		c.1484G>A	p.Gly495Glu	missense	Exon 10 of 10	ENSP00000545028.1
TFE3	ENST00000912302.1		c.1406G>A	p.Gly469Glu	missense	Exon 10 of 10	ENSP00000582361.1

Frequencies

GnomAD3 genomes

AF:

0.000110

AC:

AN:

109193

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000333

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000211

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000559

AC:

AN:

178943

AF XY:

0.0000619

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000370

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000796

AC:

AN:

1093383

Hom.:

Cov.:

AF XY:

0.0000859

AC XY:

AN XY:

360717

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26312

American (AMR)

AF:

0.0000572

AC:

AN:

34992

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19222

East Asian (EAS)

AF:

0.00

AC:

AN:

30139

South Asian (SAS)

AF:

0.0000372

AC:

AN:

53779

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40421

Middle Eastern (MID)

AF:

0.000247

AC:

AN:

4051

European-Non Finnish (NFE)

AF:

0.0000954

AC:

AN:

838582

Other (OTH)

AF:

0.0000436

AC:

AN:

45885

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.596

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000110

AC:

AN:

109193

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

31509

show subpopulations

African (AFR)

AF:

0.0000333

AC:

AN:

30038

American (AMR)

AF:

0.00

AC:

AN:

10194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2627

East Asian (EAS)

AF:

0.00

AC:

AN:

3449

South Asian (SAS)

AF:

0.00

AC:

AN:

2490

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5937

Middle Eastern (MID)

AF:

0.00

AC:

AN:

235

European-Non Finnish (NFE)

AF:

0.000211

AC:

AN:

52097

Other (OTH)

AF:

0.00

AC:

AN:

1461

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000498

Hom.:

Bravo

AF:

0.000162

ExAC

AF:

0.0000824

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Renal cell carcinoma, Xp11-associated;C5561930:Intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.78

M_CAP

Benign

0.0072

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.81

PhyloP100

0.71

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.7

REVEL

Benign

0.16

Sift

Benign

0.20

Sift4G

Benign

0.78

Polyphen

0.0040

Vest4

0.49

MVP

0.24

MPC

0.28

ClinPred

0.072

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.37

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over