12-49186832-C-T

Variant names:

• chr12-49186832-C-T
• rs587784491
• ENST00000550767.6:c.-101G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 PP2 PP3 PP5_Very_Strong

The ENST00000301071.12(TUBA1A):​c.5G>A​(p.Arg2His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TUBA1A ENST00000301071.12 missense, splice_region
• Scores: Splicing: ADA: 0.9802
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 6.09
• Publications: 14 publications found

Genes affected

TUBA1A (HGNC:20766): (tubulin alpha 1a) Microtubules of the eukaryotic cytoskeleton perform essential and diverse functions and are composed of a heterodimer of alpha and beta tubulins. The genes encoding these microtubule constituents belong to the tubulin superfamily, which is composed of six distinct families. Genes from the alpha, beta and gamma tubulin families are found in all eukaryotes. The alpha and beta tubulins represent the major components of microtubules, while gamma tubulin plays a critical role in the nucleation of microtubule assembly. There are multiple alpha and beta tubulin genes, which are highly conserved among species. This gene encodes alpha tubulin and is highly similar to the mouse and rat Tuba1 genes. Northern blot studies have shown that the gene expression is predominantly found in morphologically differentiated neurologic cells. This gene is one of three alpha-tubulin genes in a cluster on chromosome 12q. Mutations in this gene cause lissencephaly type 3 (LIS3) - a neurological condition characterized by microcephaly, intellectual disability, and early-onset epilepsy caused by defective neuronal migration. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

TUBA1B-AS1 (HGNC:56356): (TUBA1B antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-49186833-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3255105.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the TUBA1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 163 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. Gene score misZ: 5.584 (above the threshold of 3.09). Trascript score misZ: 8.7455 (above the threshold of 3.09). GenCC associations: The gene is linked to tubulinopathy, lissencephaly due to TUBA1A mutation, tubulinopathy-associated dysgyria.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 12-49186832-C-T is Pathogenic according to our data. Variant chr12-49186832-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 160161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000301071.12. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA1A	NM_006009.4	MANE Select	c.5G>A	p.Arg2His	missense splice_region	Exon 2 of 4	NP_006000.2
	TUBA1A	NM_001270400.2		c.-101G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	NP_001257329.1
	TUBA1A	NM_001270399.2		c.5G>A	p.Arg2His	missense splice_region	Exon 2 of 4	NP_001257328.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA1A	ENST00000550767.6	TSL:1	c.-101G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 5	ENSP00000446637.1
	TUBA1A	ENST00000301071.12	TSL:1 MANE Select	c.5G>A	p.Arg2His	missense splice_region	Exon 2 of 4	ENSP00000301071.7
	TUBA1A	ENST00000550767.6	TSL:1	c.-101G>A		splice_region	Exon 3 of 5	ENSP00000446637.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000108 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Lissencephaly due to TUBA1A mutation (4)
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neurodevelopmental disorder (1)
1	-	-	Seizure;C0424688:Decreased head circumference;C0557874:Global developmental delay (1)
1	-	-	TUBA1A-related disorder (1)
1	-	-	Tubulinopathy (1)
1	-	-	Tubulinopathy-associated dysgyria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	-0.066	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.62
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.081	T
Polyphen		0.81	P
Vest4		0.42
MutPred		0.58		Gain of catalytic residue at S6 (P = 9e-04)
MVP		0.87
MPC		4.2
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.43
gMVP		0.97
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.79
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: rs587784491; hg19: chr12-49580615;