11-8038876-G-T

Position:

• chr11-8038876-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000305253.8(TUB):​c.3G>T​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUB ENST00000305253.8 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUB	NM_003320.5	c.3G>T	p.Met1?	start_lost	1/13
TUB	XM_005253109.4	c.164+19518G>T		intron_variant
TUB	XM_047427512.1	c.164+19518G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUB	ENST00000305253.8	c.3G>T	p.Met1?	start_lost	1/13	1
	ENST00000526646.2	n.202+641C>A		intron_variant, non_coding_transcript_variant		3
TUB	ENST00000534099.5	c.56+19518G>T		intron_variant		2
	ENST00000528151.1	n.310C>A		non_coding_transcript_exon_variant	2/2	4

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

Invitae

May 30, 2022

This sequence change affects the initiator methionine of the TUB mRNA. The next in-frame methionine is located at codon 30. This variant is not present in population databases (gnomAD no frequency). 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: 1387700). 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
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Benign	0.97
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.22	T
MutationTaster	Benign	0.99	D;D
PROVEAN	Benign	-0.12	N
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Polyphen		0.017	B
Vest4		0.79
MutPred		0.96		Gain of catalytic residue at M1 (P = 0.0127);
MVP		0.79
ClinPred		0.33	T
GERP RS		3.4
gMVP		0.071

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-8060423;