chrX-49030447-C-A

Variant names:

• chrX-49030447-C-A
• rs149649619
• NM_006521.6:c.1439G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006521.6(TFE3):​c.1439G>T​(p.Gly480Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000278 in 1,209,577 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 119 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G480E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.00029 (0 hom. 117 hem.)
• Consequence: TFE3 NM_006521.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.50
• Publications: 4 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02219832).
• BP6: Variant X-49030447-C-A is Benign according to our data. Variant chrX-49030447-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 749357.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 17 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.1439G>T	p.Gly480Val	missense	Exon 10 of 10	NP_006512.2
	TFE3	NM_001282142.2		c.1124G>T	p.Gly375Val	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.1439G>T	p.Gly480Val	missense	Exon 10 of 10	ENSP00000314129.7	P19532-1
	TFE3	ENST00000874969.1		c.1331G>T	p.Gly444Val	missense	Exon 10 of 10	ENSP00000545028.1
	TFE3	ENST00000912302.1		c.1253G>T	p.Gly418Val	missense	Exon 10 of 10	ENSP00000582361.1

Frequencies

GnomAD3 genomes AF: 0.000153 AC: 17 AN: 111289 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000331

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000283

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000247 AC: 45 AN: 182112 AF XY: 0.000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000999

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000290 AC: 319 AN: 1098236 Hom.: 0 Cov.: 37 AF XY: 0.000322 AC XY: 117 AN XY: 363604

African (AFR) AF: 0.0000379 AC: 1 AN: 26403

American (AMR) AF: 0.000114 AC: 4 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30206

South Asian (SAS) AF: 0.000111 AC: 6 AN: 54147

European-Finnish (FIN) AF: 0.00113 AC: 46 AN: 40534

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4133

European-Non Finnish (NFE) AF: 0.000280 AC: 236 AN: 842130

Other (OTH) AF: 0.000499 AC: 23 AN: 46097

GnomAD4 genome AF: 0.000153 AC: 17 AN: 111341 Hom.: 0 Cov.: 22 AF XY: 0.0000596 AC XY: 2 AN XY: 33541

African (AFR) AF: 0.00 AC: 0 AN: 30680

American (AMR) AF: 0.00 AC: 0 AN: 10444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3497

South Asian (SAS) AF: 0.00 AC: 0 AN: 2694

European-Finnish (FIN) AF: 0.000331 AC: 2 AN: 6046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000283 AC: 15 AN: 52932

Other (OTH) AF: 0.00 AC: 0 AN: 1510

Alfa AF: 0.000437 Hom.: 3

Bravo AF: 0.000136

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

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
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.058
DANN	Benign	0.72
DEOGEN2	Uncertain	0.52	D
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.46	N
PhyloP100		-1.5
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.030
Sift	Uncertain	0.021	D
Sift4G	Benign	0.13	T
Polyphen		0.0	B
Vest4		0.22
MVP		0.043
MPC		0.039
ClinPred		0.025	T
GERP RS		-7.9
Varity_R		0.085
gMVP		0.38
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: rs149649619; hg19: chrX-48887958;