chr6-30724119-G-A

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 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 (★). ClinVar reports functional evidence for this variant: "SCV005337898: 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)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBB NM_178014.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 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: G2P, Ambry Genetics, 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: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005337898: 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).; SCV005418492: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."
• 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 complex cortical dysplasia with other brain malformations 6, multiple benign circumferential skin creases on limbs, multiple benign circumferential skin creases on limbs 1, 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 VariationId is 127190.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178014.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB	NM_178014.4	MANE Select	c.1057G>A	p.Val353Ile	missense	Exon 4 of 4	NP_821133.1	Q5SU16
	TUBB	NM_001293212.2		c.1117G>A	p.Val373Ile	missense	Exon 4 of 4	NP_001280141.1
	TUBB	NM_001293214.2		c.925G>A	p.Val309Ile	missense	Exon 3 of 3	NP_001280143.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB	ENST00000327892.13	TSL:1 MANE Select	c.1057G>A	p.Val353Ile	missense	Exon 4 of 4	ENSP00000339001.7	P07437
	TUBB	ENST00000396389.5	TSL:5	c.1003G>A	p.Val335Ile	missense	Exon 4 of 4	ENSP00000379672.1	Q5JP53
	TUBB	ENST00000940307.1		c.946G>A	p.Val316Ile	missense	Exon 3 of 3	ENSP00000610366.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Complex cortical dysplasia with other brain malformations 6 (2)
1	-	-	Complex cortical dysplasia with other brain malformations 6;C4551592:Multiple benign circumferential skin creases on limbs 1 (1)
1	-	-	not provided (1)
1	-	-	TUBB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.71	N
PhyloP100		9.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.56
Sift4G	Benign	0.36	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
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;