X-49030297-T-C

Variant names:

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

Variant summary

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

The NM_006521.6(TFE3):​c.1589A>G​(p.Glu530Gly) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E530V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000042 (0 hom., 0 hem., cov: 11)
  • Exomes 𝑓: 0.00012 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: TFE3 NM_006521.6 missense
• Clinical Significance: Not reported in ClinVar
• 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, PanelApp Australia
• 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>G	p.Glu530Gly	missense	Exon 10 of 10	NP_006512.2
	TFE3	NM_001282142.2		c.1274A>G	p.Glu425Gly	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>G	p.Glu530Gly	missense	Exon 10 of 10	ENSP00000314129.7	P19532-1
	TFE3	ENST00000874969.1		c.1481A>G	p.Glu494Gly	missense	Exon 10 of 10	ENSP00000545028.1
	TFE3	ENST00000912302.1		c.1403A>G	p.Glu468Gly	missense	Exon 10 of 10	ENSP00000582361.1

Frequencies

GnomAD3 genomes AF: 0.0000422 AC: 2 AN: 47392 Hom.: 0 Cov.: 11

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000247

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000962

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: 0.000124 AC: 60 AN: 485230 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 151244

⚠️ 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: 12258

American (AMR) AF: 0.000345 AC: 6 AN: 17383

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7583

East Asian (EAS) AF: 0.00 AC: 0 AN: 8602

South Asian (SAS) AF: 0.000216 AC: 6 AN: 27796

European-Finnish (FIN) AF: 0.0000520 AC: 1 AN: 19244

Middle Eastern (MID) AF: 0.000455 AC: 1 AN: 2200

European-Non Finnish (NFE) AF: 0.000110 AC: 41 AN: 372507

Other (OTH) AF: 0.000283 AC: 5 AN: 17657

⚠️ 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: 0.0000422 AC: 2 AN: 47398 Hom.: 0 Cov.: 11 AF XY: 0.00 AC XY: 0 AN XY: 11976

⚠️ 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: 11911

American (AMR) AF: 0.000247 AC: 1 AN: 4052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1278

East Asian (EAS) AF: 0.00 AC: 0 AN: 1743

South Asian (SAS) AF: 0.000964 AC: 1 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: 24758

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.

Alfa AF: 0.00506 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.17
Sift	Uncertain	0.016	D
Sift4G	Benign	0.29	T
Polyphen		0.97	D
Vest4		0.55
MutPred		0.31		Loss of helix (P = 0.0196)
MVP		0.25
MPC		0.18
ClinPred		0.81	D
GERP RS		4.5
Varity_R		0.22
gMVP		0.22
Mutation Taster		=94/6	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;