rs587777356

Variant names:

• chr6-30724119-G-A
• rs587777356
• NM_178014.4:c.1057G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• complex cortical dysplasia with other brain malformations 6

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• multiple benign circumferential skin creases on limbs 1

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, G2P
• TUBB3-related tubulinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
• multiple benign circumferential skin creases on limbs

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000272540 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the TUBB gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 26 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 5.6252 (above the threshold of 3.09). Trascript score misZ: 8.3435 (above the threshold of 3.09). GenCC associations: The gene is linked to TUBB3-related tubulinopathy, multiple benign circumferential skin creases on limbs 1, complex cortical dysplasia with other brain malformations 6, multiple benign circumferential skin creases on limbs.
• 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 VariationId is 127190.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB	NM_178014.4	c.1057G>A	p.Val353Ile	missense_variant	Exon 4 of 4	ENST00000327892.13	NP_821133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB	ENST00000327892.13	c.1057G>A	p.Val353Ile	missense_variant	Exon 4 of 4	1	NM_178014.4	ENSP00000339001.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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.

Dec 27, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Assumed de novo, but without confirmation of paternity and maternity.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc).

TUBB-related disorder Pathogenic:1

Jun 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
LIST_S2	Benign	0.0	.;.;.;.
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.71	N;.;.;.
PhyloP100		9.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.37	N;N;N;N
Sift	Pathogenic	0.0	.;.;.;.
Sift4G	Benign	0.36	T;T;T;T
Vest4		0.62
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
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777356; hg19: chr6-30691896;