rs587784493

Variant names:

• chr12-49185608-G-C
• rs587784493
• NM_006009.4:c.758C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-49185608-G-C
• chr12-49185608-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_006009.4(TUBA1A):​c.758C>G​(p.Thr253Arg) variant causes a missense change involving the alteration of a 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T253K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBA1A NM_006009.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.21
• Publications: 1 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-49185608-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1349068.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: MetaRNN computational evidence supports a deleterious effect, 0.886

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006009.4. 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.758C>G	p.Thr253Arg	missense	Exon 4 of 4	NP_006000.2
	TUBA1A	NM_001270399.2		c.758C>G	p.Thr253Arg	missense	Exon 4 of 4	NP_001257328.1
	TUBA1A	NM_001270400.2		c.653C>G	p.Thr218Arg	missense	Exon 4 of 4	NP_001257329.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA1A	ENST00000301071.12	TSL:1 MANE Select	c.758C>G	p.Thr253Arg	missense	Exon 4 of 4	ENSP00000301071.7
	TUBA1A	ENST00000550767.6	TSL:1	c.653C>G	p.Thr218Arg	missense	Exon 5 of 5	ENSP00000446637.1
	TUBA1A	ENST00000295766.9	TSL:2	c.758C>G	p.Thr253Arg	missense	Exon 4 of 4	ENSP00000439020.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Lissencephaly due to TUBA1A mutation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	0.90	L
PhyloP100		9.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.016	D
Polyphen		0.52	P
Vest4		0.89
MutPred		0.49		Gain of catalytic residue at N249 (P = 0.0047)
MVP		0.93
MPC		2.6
ClinPred		0.97	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.98
Mutation Taster		=13/87	disease causing

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: rs587784493; hg19: chr12-49579391;