11-8038925-A-G

Variant names:

• chr11-8038925-A-G
• rs1942692795
• ENST00000305253.8:c.52A>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 rank	MANE	Protein	UniProt
TUB	NM_003320.5	c.52A>G	p.Thr18Ala	missense_variant	Exon 1 of 13		NP_003311.2
TUB	XM_005253109.4	c.164+19567A>G		intron_variant	Intron 1 of 11		XP_005253166.1
TUB	XM_047427512.1	c.164+19567A>G		intron_variant	Intron 1 of 11		XP_047283468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUB	ENST00000305253.8	c.52A>G	p.Thr18Ala	missense_variant	Exon 1 of 13	1		ENSP00000305426.4
TUB	ENST00000534099.5	c.56+19567A>G		intron_variant	Intron 1 of 11	2		ENSP00000434400.1
ENSG00000254921	ENST00000528151.1	n.261T>C		non_coding_transcript_exon_variant	Exon 2 of 2	4
ENSG00000254921	ENST00000526646.2	n.202+592T>C		intron_variant	Intron 1 of 1	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

Jun 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;