11-8038921-CGAGACAGG-C

Position:

chr11-8038921-CGAGACAGG-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PVS1_StrongPM2BS1_Supporting

The NM_003320.5(TUB):c.51_58delGACAGGGA(p.Glu17fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000496 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

TUB
NM_003320.5 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 3.92

Variant links:

Genes affected

TUB (HGNC:12406): (TUB bipartite transcription factor) This gene encodes a member of the Tubby family of bipartite transcription factors. The encoded protein may play a role in obesity and sensorineural degradation. The crystal structure has been determined for a similar protein in mouse, and it functions as a membrane-bound transcription regulator that translocates to the nucleus in response to phosphoinositide hydrolysis. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

TUB links:

ENSG00000254921 (HGNC:):

ENSG00000254921 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.97 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000046 (7/152232) while in subpopulation EAS AF= 0.000967 (5/5170). AF 95% confidence interval is 0.000381. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
TUB	NM_003320.5 linkuse as main transcript	c.51_58delGACAGGGA	p.Glu17fs	frameshift_variant	1/13	NP_003311.2	P50607-2
TUB	XM_005253109.4 linkuse as main transcript	c.164+19566_164+19573delGACAGGGA		intron_variant		XP_005253166.1
TUB	XM_047427512.1 linkuse as main transcript	c.164+19566_164+19573delGACAGGGA		intron_variant		XP_047283468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
TUB	ENST00000305253.8 linkuse as main transcript	c.51_58delGACAGGGA	p.Glu17fs	frameshift_variant	1/13	1	ENSP00000305426.4	P50607-2
TUB	ENST00000534099.5 linkuse as main transcript	c.56+19566_56+19573delGACAGGGA		intron_variant		2	ENSP00000434400.1	E9PQR4
ENSG00000254921	ENST00000528151.1 linkuse as main transcript	n.257_264delCCTGTCTC		non_coding_transcript_exon_variant	2/2	4
ENSG00000254921	ENST00000526646.2 linkuse as main transcript	n.202+588_202+595delCCTGTCTC		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000965

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000111

AC:

AN:

251416

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00152

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000499

AC:

AN:

1461802

Hom.:

AF XY:

0.0000578

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00169

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000967

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000945

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

TUB-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2024

The TUB c.51_58del8 variant is predicted to result in a frameshift and premature protein termination (p.Glu17Aspfs*53). This variant was reported in a study of carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases (Hanany et al. 2020. PubMed ID: 31964843, Table S3). This variant is reported in 0.15% of alleles in individuals of East Asian descent in gnomAD. Since the role of this gene is currently unclear to human diseases, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2022

This sequence change creates a premature translational stop signal (p.Glu17Aspfs*53) in the TUB gene. However, it is currently unclear if variants that occur in this region of the gene cause disease. This variant is present in population databases (rs752465674, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with TUB-related conditions. ClinVar contains an entry for this variant (Variation ID: 1069023). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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