NM_006521.6:c.1589A>T

Variant names:

• chrX-49030297-T-A
• rs1286561719
• NM_006521.6:c.1589A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_006521.6(TFE3):​c.1589A>T​(p.Glu530Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., 0 hem., cov: 11)
  • Exomes 𝑓: 0.000060 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: TFE3 NM_006521.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.93
• Publications: 1 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 0 ACMG points.

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.1589A>T	p.Glu530Val	missense	Exon 10 of 10	NP_006512.2
	TFE3	NM_001282142.2		c.1274A>T	p.Glu425Val	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.1589A>T	p.Glu530Val	missense	Exon 10 of 10	ENSP00000314129.7	P19532-1
	TFE3	ENST00000874969.1		c.1481A>T	p.Glu494Val	missense	Exon 10 of 10	ENSP00000545028.1
	TFE3	ENST00000912302.1		c.1403A>T	p.Glu468Val	missense	Exon 10 of 10	ENSP00000582361.1

Frequencies

GnomAD3 genomes AF: 0.0000211 AC: 1 AN: 47392 Hom.: 0 Cov.: 11

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000598 AC: 29 AN: 485343 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 151399

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 12253

American (AMR) AF: 0.00 AC: 0 AN: 17397

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7587

East Asian (EAS) AF: 0.000233 AC: 2 AN: 8595

South Asian (SAS) AF: 0.00 AC: 0 AN: 28021

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19304

Middle Eastern (MID) AF: 0.000454 AC: 1 AN: 2202

European-Non Finnish (NFE) AF: 0.0000671 AC: 25 AN: 372314

Other (OTH) AF: 0.0000566 AC: 1 AN: 17670

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000211 AC: 1 AN: 47398 Hom.: 0 Cov.: 11 AF XY: 0.00 AC XY: 0 AN XY: 11980

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 11912

American (AMR) AF: 0.00 AC: 0 AN: 4054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1276

East Asian (EAS) AF: 0.000576 AC: 1 AN: 1736

South Asian (SAS) AF: 0.00 AC: 0 AN: 1037

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1543

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 133

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 24764

Other (OTH) AF: 0.00 AC: 0 AN: 638

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	TFE3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.16
Sift	Benign	0.043	D
Sift4G	Benign	0.15	T
Polyphen		0.97	D
Vest4		0.63
MutPred		0.39		Loss of solvent accessibility (P = 0.0224)
MVP		0.31
MPC		0.18
ClinPred		0.88	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.36
Mutation Taster		=95/5	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

dbSNP: rs1286561719; hg19: chrX-48887808;