11-8038925-A-G

Position:

• chr11-8038925-A-G

Variant summary

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

The NM_003320.5(TUB):​c.52A>G​(p.Thr18Ala) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUB NM_003320.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92

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]

ENSG00000254921 (HGNC:):

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=0.23479751).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUB	NM_003320.5	c.52A>G	p.Thr18Ala	missense_variant	1/13		NP_003311.2
TUB	XM_005253109.4	c.164+19567A>G		intron_variant			XP_005253166.1
TUB	XM_047427512.1	c.164+19567A>G		intron_variant			XP_047283468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUB	ENST00000305253.8	c.52A>G	p.Thr18Ala	missense_variant	1/13	1		ENSP00000305426.4
TUB	ENST00000534099.5	c.56+19567A>G		intron_variant		2		ENSP00000434400.1
ENSG00000254921	ENST00000528151.1	n.261T>C		non_coding_transcript_exon_variant	2/2	4
ENSG00000254921	ENST00000526646.2	n.202+592T>C		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 04, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 933290). This variant has not been reported in the literature in individuals affected with TUB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 18 of the TUB protein (p.Thr18Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Benign	-0.064
Eigen_PC	Benign	0.043
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.38	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.62	T
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.20
Sift	Benign	0.27	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.34	B
Vest4		0.36
MutPred		0.25		Loss of sheet (P = 0.0104);
MVP		0.91
MPC		0.18
ClinPred		0.81	D
GERP RS		3.8
gMVP		0.081

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1942692795; hg19: chr11-8060472;