dbSNP rs6939861: TFEB:c.-23+47C>T (chr6-41735303-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.346

Publications

8 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271944.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TFEB	NM_001271944.2	MANE Select	c.-23+47C>T	intron	N/A	NP_001258873.1	P19484-1
TFEB	NM_001167827.3		c.20+843C>T	intron	N/A	NP_001161299.2	B0QYS6
TFEB	NM_001271943.2		c.-23+47C>T	intron	N/A	NP_001258872.1	P19484-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TFEB	ENST00000373033.6	TSL:1 MANE Select	c.-23+47C>T	intron	N/A	ENSP00000362124.1	P19484-1
TFEB	ENST00000358871.6	TSL:1	c.20+843C>T	intron	N/A	ENSP00000351742.2	B0QYS6
TFEB	ENST00000861508.1		c.-129+47C>T	intron	N/A	ENSP00000531567.1

Frequencies

GnomAD3 genomes

AF:

0.244

AC:

36967

AN:

151284

Hom.:

4603

Cov.:

show subpopulations

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.:

AF XY:

0.262

AC XY:

100625

AN XY:

384596

show subpopulations

African (AFR)

AF:

0.168

AC:

2652

AN:

15784

American (AMR)

AF:

0.256

AC:

252

AN:

984

Ashkenazi Jewish (ASJ)

AF:

0.212

AC:

1089

AN:

5148

East Asian (EAS)

AF:

0.350

AC:

1272

AN:

3630

South Asian (SAS)

AF:

0.260

AC:

4271

AN:

16452

European-Finnish (FIN)

AF:

0.283

AC:

AN:

276

Middle Eastern (MID)

AF:

0.273

AC:

444

AN:

1626

European-Non Finnish (NFE)

AF:

0.264

AC:

201037

AN:

761602

Other (OTH)

AF:

0.257

AC:

7015

AN:

27278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

8666

17332

25999

34665

43331

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9232

18464

27696

36928

46160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.244

AC:

36991

AN:

151394

Hom.:

4605

Cov.:

AF XY:

0.245

AC XY:

18139

AN XY:

74000

show subpopulations

African (AFR)

AF:

0.179

AC:

7416

AN:

41424

American (AMR)

AF:

0.243

AC:

3707

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.231

AC:

797

AN:

3456

East Asian (EAS)

AF:

0.351

AC:

1801

AN:

5130

South Asian (SAS)

AF:

0.262

AC:

1261

AN:

4816

European-Finnish (FIN)

AF:

0.271

AC:

2807

AN:

10354

Middle Eastern (MID)

AF:

0.329

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.270

AC:

18306

AN:

67684

Other (OTH)

AF:

0.268

AC:

564

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

1441

2882

4324

5765

7206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

400

800

1200

1600

2000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.255

Hom.:

2134

Bravo

AF:

0.240

Asia WGS

AF:

0.302

AC:

1018

AN:

3364

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.6

(source)

DANN

Benign

0.88

PhyloP100

-0.35

PromoterAI

-0.036

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over