X-49030447-C-T

Position:

chrX-49030447-C-T

Variant summary

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

The NM_006521.6(TFE3):c.1439G>A(p.Gly480Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,209,525 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000025 ( 0 hom. 5 hem. )

Consequence

TFE3
NM_006521.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.50

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=0.051671445).

BP6

Variant X-49030447-C-T is Benign according to our data. Variant chrX-49030447-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2589029.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-49030447-C-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TFE3	NM_006521.6 linkuse as main transcript	c.1439G>A	p.Gly480Glu	missense_variant	10/10	ENST00000315869.8	NP_006512.2
TFE3	NM_001282142.2 linkuse as main transcript	c.1124G>A	p.Gly375Glu	missense_variant	10/10		NP_001269071.1
TFE3	XM_024452432.2 linkuse as main transcript	c.*69G>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 linkuse as main transcript	c.1439G>A	p.Gly480Glu	missense_variant	10/10	1	NM_006521.6	ENSP00000314129	P1	P19532-1
TFE3	ENST00000493583.5 linkuse as main transcript	c.*1044G>A		3_prime_UTR_variant, NMD_transcript_variant	10/10	2		ENSP00000476976		P19532-2

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111289

Hom.:

Cov.:

AF XY:

0.0000597

AC XY:

AN XY:

33479

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000959

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000604

AC:

AN:

182112

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

67316

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000182

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:

0.0000620

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000255

AC:

AN:

1098236

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363604

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.000199

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000190

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000180

AC:

AN:

111289

Hom.:

Cov.:

AF XY:

0.0000597

AC XY:

AN XY:

33479

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000189

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.0000494

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

Jun 30, 2023

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

0.10

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.042

DANN

Benign

0.72

DEOGEN2

Benign

0.35

FATHMM_MKL

Benign

0.071

LIST_S2

Benign

0.52

M_CAP

Benign

0.0036

MetaRNN

Benign

0.052

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.64

REVEL

Benign

0.024

Sift

Benign

0.11

Sift4G

Benign

0.54

Polyphen

0.0

Vest4

0.23

MutPred

0.29

Loss of sheet (P = 0.0315);

MVP

0.068

MPC

0.040

ClinPred

0.20

GERP RS

-7.9

Varity_R

0.066

gMVP

0.38

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