Genetic Variant TFE3:p.Glu530del (chrX-49030294-CCCT-C) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP3BP6_ModerateBS2

The NM_006521.6(TFE3):c.1589_1591delAGG(p.Glu530del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000635 in 1,201,310 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 232 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., 6 hem., cov: 11)

Exomes 𝑓: 0.00066 ( 0 hom. 226 hem. )

Consequence

TFE3
NM_006521.6 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.93

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 -7 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_006521.6

BP6

Variant X-49030294-CCCT-C is Benign according to our data. Variant chrX-49030294-CCCT-C is described in ClinVar as [Benign]. Clinvar id is 3176514.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFE3	NM_006521.6 link	c.1589_1591delAGG	p.Glu530del	disruptive_inframe_deletion	Exon 10 of 10	ENST00000315869.8	NP_006512.2	P19532-1A0A024QZ23
TFE3	NM_001282142.2 link	c.1274_1276delAGG	p.Glu425del	disruptive_inframe_deletion	Exon 10 of 10		NP_001269071.1	P19532B4DIA5
TFE3	XM_024452432.2 link	c.219_221delAGG		3_prime_UTR_variant	Exon 11 of 11		XP_024308200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TFE3	ENST00000315869.8 link	c.1589_1591delAGG	p.Glu530del	disruptive_inframe_deletion	Exon 10 of 10	1	NM_006521.6	ENSP00000314129.7	P19532-1
TFE3	ENST00000493583.5 link	n.1194_1196delAGG		non_coding_transcript_exon_variant	Exon 10 of 10	2		ENSP00000476976.1	P19532-2
TFE3	ENST00000493583.5 link	n.1194_1196delAGG		3_prime_UTR_variant	Exon 10 of 10	2		ENSP00000476976.1	P19532-2
TFE3	ENST00000495940.2 link	n.218_220delAGG		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000339

AC:

AN:

109189

Hom.:

Cov.:

AF XY:

0.000190

AC XY:

AN XY:

31509

show subpopulations

Gnomad AFR

AF:

0.0000666

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000633

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000173

AC:

AN:

178943

Hom.:

AF XY:

0.000139

AC XY:

AN XY:

64665

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000148

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000190

Gnomad NFE exome

AF:

0.000290

Gnomad OTH exome

AF:

0.000227

GnomAD4 exome

AF:

0.000665

AC:

726

AN:

1092070

Hom.:

AF XY:

0.000628

AC XY:

226

AN XY:

359926

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000143

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000124

Gnomad4 NFE exome

AF:

0.000835

Gnomad4 OTH exome

AF:

0.000371

GnomAD4 genome

AF:

0.000339

AC:

AN:

109240

Hom.:

Cov.:

AF XY:

0.000190

AC XY:

AN XY:

31570

show subpopulations

Gnomad4 AFR

AF:

0.0000664

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000634

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000800

Hom.:

Bravo

AF:

0.000332

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Oct 19, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

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