rs587777356

Positions:

• chr6-30724119-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_178014.4(TUBB):​c.1057G>A​(p.Val353Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBB NM_178014.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 9.64

Genes affected

TUBB (HGNC:20778): (tubulin beta class I) This gene encodes a beta tubulin protein. This protein forms a dimer with alpha tubulin and acts as a structural component of microtubules. Mutations in this gene cause cortical dysplasia, complex, with other brain malformations 6. Alternative splicing results in multiple splice variants. There are multiple pseudogenes for this gene on chromosomes 1, 6, 7, 8, 9, and 13. [provided by RefSeq, Jun 2014]

TUBB (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBB. . Gene score misZ 5.6252 (greater than the threshold 3.09). Trascript score misZ 8.3435 (greater than threshold 3.09). GenCC has associacion of gene with multiple benign circumferential skin creases on limbs 1, complex cortical dysplasia with other brain malformations 6, multiple benign circumferential skin creases on limbs, TUBB3-related tubulinopathy.
• PP5: Variant 6-30724119-G-A is Pathogenic according to our data. Variant chr6-30724119-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 127190.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-30724119-G-A is described in UniProt as null. Variant chr6-30724119-G-A is described in UniProt as null. Variant chr6-30724119-G-A is described in UniProt as null. Variant chr6-30724119-G-A is described in UniProt as null. Variant chr6-30724119-G-A is described in UniProt as null. Variant chr6-30724119-G-A is described in UniProt as null. Variant chr6-30724119-G-A is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB	NM_178014.4	c.1057G>A	p.Val353Ile	missense_variant	4/4	ENST00000327892.13	NP_821133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB	ENST00000327892.13	c.1057G>A	p.Val353Ile	missense_variant	4/4	1	NM_178014.4	ENSP00000339001.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 6 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 27, 2012	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Pathogenic and reported on 07-31-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Complex cortical dysplasia with other brain malformations 6;C4551592:Multiple benign circumferential skin creases on limbs 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PP2+PS4_Supporting+PM6+PP4+PS3_Supporting+BP4 -

TUBB-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2024

The TUBB c.1057G>A variant is predicted to result in the amino acid substitution p.Val353Ile. This variant was reported in an individual with Microcephaly and it occurred de novo in the patient (Breuss et al 2012. PubMed ID: 23246003). Functional studies demonstrated that this variant may disrupt microtubule meshwork formation and lead to a migration defect (Ngo L et al 2014. PubMed ID: 24833723). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.;T;.
Eigen	Benign	0.027
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.71	N;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.37	N;N;N;N
REVEL	Uncertain	0.56
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.0060	B;.;.;.
Vest4		0.62
MutPred		0.46		Gain of ubiquitination at K350 (P = 0.1375);.;.;.;
MVP		0.98
MPC		1.5
ClinPred		0.89	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.25
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777356; hg19: chr6-30691896;