rs782272958

Variant names:

• chrX-49030170-T-C
• rs782272958
• NM_006521.6:c.1716A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_006521.6(TFE3):​c.1716A>G​(p.Glu572Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000166 in 1,205,876 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000016 (0 hom. 5 hem.)
• Consequence: TFE3 NM_006521.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.507
• Publications: 0 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant X-49030170-T-C is Benign according to our data. Variant chrX-49030170-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 732446.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.507 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 18 XL,AD gene.

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.1716A>G	p.Glu572Glu	synonymous	Exon 10 of 10	NP_006512.2
	TFE3	NM_001282142.2		c.1401A>G	p.Glu467Glu	synonymous	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.1716A>G	p.Glu572Glu	synonymous	Exon 10 of 10	ENSP00000314129.7	P19532-1
	TFE3	ENST00000874969.1		c.1608A>G	p.Glu536Glu	synonymous	Exon 10 of 10	ENSP00000545028.1
	TFE3	ENST00000912302.1		c.1530A>G	p.Glu510Glu	synonymous	Exon 10 of 10	ENSP00000582361.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111714 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000950

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000291 AC: 5 AN: 171937 AF XY: 0.0000171

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: 0.0000525

Gnomad OTH exome AF: 0.000235

GnomAD4 exome AF: 0.0000165 AC: 18 AN: 1094107 Hom.: 0 Cov.: 31 AF XY: 0.0000139 AC XY: 5 AN XY: 360139

African (AFR) AF: 0.0000760 AC: 2 AN: 26328

American (AMR) AF: 0.00 AC: 0 AN: 34424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19145

East Asian (EAS) AF: 0.00 AC: 0 AN: 30157

South Asian (SAS) AF: 0.00 AC: 0 AN: 53514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40348

Middle Eastern (MID) AF: 0.00148 AC: 6 AN: 4058

European-Non Finnish (NFE) AF: 0.00000952 AC: 8 AN: 840259

Other (OTH) AF: 0.0000436 AC: 2 AN: 45874

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111769 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 33963

African (AFR) AF: 0.00 AC: 0 AN: 30856

American (AMR) AF: 0.0000949 AC: 1 AN: 10540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3501

South Asian (SAS) AF: 0.00 AC: 0 AN: 2710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6122

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52980

Other (OTH) AF: 0.00 AC: 0 AN: 1528

Alfa AF: 0.0000480 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.9
DANN	Benign	0.77
PhyloP100		-0.51
Mutation Taster		=99/1	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: rs782272958; hg19: chrX-48887681; COSMIC: COSV59947815; COSMIC: COSV59947815;