Variant 6-41690745-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001271944.2(TFEB):c.386A>G(p.His129Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000689 in 1,451,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

TFEB
NM_001271944.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.07

Variant links:

Genes affected

TFEB (HGNC:11753): (transcription factor EB) Enables DNA-binding transcription factor activity; enzyme binding activity; and transcription cis-regulatory region binding activity. Involved in several processes, including cellular response to amino acid starvation; lysosome localization; and positive regulation of autophagy. Located in cytosol; lysosomal membrane; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TFEB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16871819).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFEB	NM_001271944.2 link	c.386A>G	p.His129Arg	missense_variant	3/9	ENST00000373033.6	NP_001258873.1	P19484-1A0A024RCY3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFEB	ENST00000373033.6 link	c.386A>G	p.His129Arg	missense_variant	3/9	1	NM_001271944.2	ENSP00000362124.1		P19484-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000817

AC:

AN:

244724

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

132130

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000904

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.00000689

AC:

AN:

1451206

Hom.:

Cov.:

AF XY:

0.00000833

AC XY:

AN XY:

720394

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000724

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2024

The c.386A>G (p.H129R) alteration is located in exon 4 (coding exon 2) of the TFEB gene. This alteration results from a A to G substitution at nucleotide position 386, causing the histidine (H) at amino acid position 129 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.067

T;D;T;D;D;.;T;.;.

Eigen

Benign

-0.065

Eigen_PC

Benign

0.046

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.76

T;.;T;T;.;T;T;T;T

M_CAP

Benign

0.0067

MetaRNN

Benign

0.17

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;L;.;L;L;.;.;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.8

N;N;N;N;N;N;N;N;N

REVEL

Benign

0.086

Sift

Uncertain

0.0070

D;D;D;D;D;D;D;D;D

Sift4G

Benign

0.29

T;T;T;T;T;T;.;.;.

Polyphen

0.073

B;B;B;B;B;.;.;.;.

Vest4

0.21

MutPred

0.29

Gain of MoRF binding (P = 0.0071);.;.;.;.;.;.;.;.;

MVP

0.12

MPC

0.57

ClinPred

0.13

GERP RS

4.0

Varity_R

0.29

gMVP

0.58

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over