6-41686140-G-T

Position:

• chr6-41686140-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000373033.6(TFEB):​c.901C>A​(p.His301Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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)
• Consequence: TFEB ENST00000373033.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.14

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15739822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFEB	NM_001271944.2	c.901C>A	p.His301Asn	missense_variant	8/9	ENST00000373033.6	NP_001258873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFEB	ENST00000373033.6	c.901C>A	p.His301Asn	missense_variant	8/9	1	NM_001271944.2	ENSP00000362124	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2023

The c.901C>A (p.H301N) alteration is located in exon 9 (coding exon 7) of the TFEB gene. This alteration results from a C to A substitution at nucleotide position 901, causing the histidine (H) at amino acid position 301 to be replaced by an asparagine (N). 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	0.14
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.011	T;T;T;T;T;.;T
Eigen	Benign	-0.050
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D;.;D;D;D;.
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	.;.;L;.;L;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.39	N;N;N;N;N;N;N
REVEL	Benign	0.060
Sift	Benign	0.059	T;D;T;T;T;T;T
Sift4G	Benign	0.10	T;T;T;T;T;T;T
Polyphen		0.15, 0.23	.;.;B;B;B;B;B
Vest4		0.25, 0.29, 0.28, 0.30, 0.28, 0.28
MutPred		0.18		.;.;.;Loss of methylation at R318 (P = 0.1312);.;.;.;
MVP		0.093
MPC		0.58
ClinPred		0.70	D
GERP RS		4.6
Varity_R		0.25
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-41653878;