X-49030435-G-A

Position:

chrX-49030435-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_006521.6(TFE3):c.1451C>T(p.Ala484Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,209,222 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 84 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., 39 hem., cov: 22)

Exomes 𝑓: 0.00014 ( 0 hom. 45 hem. )

Consequence

TFE3
NM_006521.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.768

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068257153).

BP6

Variant X-49030435-G-A is Benign according to our data. Variant chrX-49030435-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3176513.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-49030435-G-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 39 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFE3	NM_006521.6 link	c.1451C>T	p.Ala484Val	missense_variant	10/10	ENST00000315869.8	NP_006512.2	P19532-1A0A024QZ23
TFE3	NM_001282142.2 link	c.1136C>T	p.Ala379Val	missense_variant	10/10		NP_001269071.1	P19532B4DIA5
TFE3	XM_024452432.2 link	c.*81C>T		3_prime_UTR_variant	11/11		XP_024308200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TFE3	ENST00000315869.8 link	c.1451C>T	p.Ala484Val	missense_variant	10/10	1	NM_006521.6	ENSP00000314129.7	P19532-1
TFE3	ENST00000493583.5 link	n.*1056C>T		non_coding_transcript_exon_variant	10/10	2		ENSP00000476976.1	P19532-2
TFE3	ENST00000493583.5 link	n.*1056C>T		3_prime_UTR_variant	10/10	2		ENSP00000476976.1	P19532-2

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

135

AN:

110977

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

33187

show subpopulations

Gnomad AFR

AF:

0.00433

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000960

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:

0.0000378

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000280

AC:

AN:

182198

Hom.:

AF XY:

0.000208

AC XY:

AN XY:

67284

show subpopulations

Gnomad AFR exome

AF:

0.00319

Gnomad AMR exome

AF:

0.000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000137

AC:

150

AN:

1098191

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

363565

show subpopulations

Gnomad4 AFR exome

AF:

0.00458

Gnomad4 AMR exome

AF:

0.000227

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:

0.00000594

Gnomad4 OTH exome

AF:

0.000347

GnomAD4 genome

AF:

0.00122

AC:

135

AN:

111031

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

33251

show subpopulations

Gnomad4 AFR

AF:

0.00432

Gnomad4 AMR

AF:

0.0000959

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000378

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.00142

ESP6500AA

AF:

0.00469

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000247

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.47

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.63

M_CAP

Benign

0.041

MetaRNN

Benign

0.0068

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.78

REVEL

Benign

0.023

Sift

Benign

0.29

Sift4G

Benign

0.16

Polyphen

0.15

Vest4

0.17

MVP

0.46

MPC

0.034

ClinPred

0.0087

GERP RS

3.1

Varity_R

0.12

gMVP

0.31

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over