X-49030294-CCCTCCT-C

Variant names:

• chrX-49030294-CCCTCCT-C
• rs782080222
• NM_006521.6:c.1586_1591delAGGAGG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_006521.6(TFE3):​c.1586_1591delAGGAGG​(p.Glu529_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 0.000000915 in 1,093,380 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 11)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: TFE3 NM_006521.6 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.47
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_006521.6

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.1586_1591delAGGAGG	p.Glu529_Glu530del	disruptive_inframe_deletion	Exon 10 of 10	NP_006512.2
	TFE3	NM_001282142.2		c.1271_1276delAGGAGG	p.Glu424_Glu425del	disruptive_inframe_deletion	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.1586_1591delAGGAGG	p.Glu529_Glu530del	disruptive_inframe_deletion	Exon 10 of 10	ENSP00000314129.7	P19532-1
	TFE3	ENST00000874969.1		c.1478_1483delAGGAGG	p.Glu493_Glu494del	disruptive_inframe_deletion	Exon 10 of 10	ENSP00000545028.1
	TFE3	ENST00000912302.1		c.1400_1405delAGGAGG	p.Glu467_Glu468del	disruptive_inframe_deletion	Exon 10 of 10	ENSP00000582361.1

Frequencies

GnomAD3 genomes Cov.: 11

GnomAD2 exomes AF: 0.00000559 AC: 1 AN: 178943 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1093380 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 360714

⚠️ 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: 26311

American (AMR) AF: 0.00 AC: 0 AN: 34992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19222

East Asian (EAS) AF: 0.00 AC: 0 AN: 30139

South Asian (SAS) AF: 0.00 AC: 0 AN: 53779

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40421

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4051

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 838580

Other (OTH) AF: 0.00 AC: 0 AN: 45885

⚠️ 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 Cov.: 11

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs782080222; hg19: chrX-48887805;