rs6939861

Positions:

• chr6-41735303-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001271944.2(TFEB):​c.-23+47C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 984,174 control chromosomes in the GnomAD database, including 33,442 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (4605 hom., cov: 32)
  • Exomes 𝑓: 0.26 (28837 hom.)
• Consequence: TFEB NM_001271944.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.346

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFEB	NM_001271944.2	c.-23+47C>T		intron_variant		ENST00000373033.6	NP_001258873.1
TFEB	NM_001167827.3	c.20+843C>T		intron_variant			NP_001161299.2
TFEB	NM_001271943.2	c.-23+47C>T		intron_variant			NP_001258872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFEB	ENST00000373033.6	c.-23+47C>T		intron_variant		1	NM_001271944.2	ENSP00000362124	P1
TFEB	ENST00000358871.6	c.20+843C>T		intron_variant		1		ENSP00000351742

Frequencies

GnomAD3 genomes AF: 0.244 AC: 36967 AN: 151284 Hom.: 4603 Cov.: 32

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.351

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.271

Gnomad MID AF: 0.324

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.268

GnomAD4 exome AF: 0.262 AC: 218110 AN: 832780 Hom.: 28837 Cov.: 28 AF XY: 0.262 AC XY: 100625 AN XY: 384596

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.256

Gnomad4 ASJ exome AF: 0.212

Gnomad4 EAS exome AF: 0.350

Gnomad4 SAS exome AF: 0.260

Gnomad4 FIN exome AF: 0.283

Gnomad4 NFE exome AF: 0.264

Gnomad4 OTH exome AF: 0.257

GnomAD4 genome AF: 0.244 AC: 36991 AN: 151394 Hom.: 4605 Cov.: 32 AF XY: 0.245 AC XY: 18139 AN XY: 74000

Gnomad4 AFR AF: 0.179

Gnomad4 AMR AF: 0.243

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.351

Gnomad4 SAS AF: 0.262

Gnomad4 FIN AF: 0.271

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.268

Alfa AF: 0.255 Hom.: 1754

Bravo AF: 0.240

Asia WGS AF: 0.302 AC: 1018 AN: 3364

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.6
DANN	Benign	0.88

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs6939861; hg19: chr6-41703041;