12-49186397-T-G

Variant names:

• chr12-49186397-T-G
• rs1056875
• NM_006009.4:c.288A>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_006009.4(TUBA1A):​c.288A>C​(p.Lys96Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K96K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: TUBA1A NM_006009.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.912
• Publications: 24 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006009.4
• PM2: Very rare variant in population databases, with high coverage
• 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.

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.288A>C	p.Lys96Asn	missense	Exon 3 of 4	NP_006000.2
	TUBA1A	NM_001270399.2		c.288A>C	p.Lys96Asn	missense	Exon 3 of 4	NP_001257328.1
	TUBA1A	NM_001270400.2		c.183A>C	p.Lys61Asn	missense	Exon 3 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.288A>C	p.Lys96Asn	missense	Exon 3 of 4	ENSP00000301071.7
	TUBA1A	ENST00000550767.6	TSL:1	c.183A>C	p.Lys61Asn	missense	Exon 4 of 5	ENSP00000446637.1
	TUBA1A	ENST00000295766.9	TSL:2	c.288A>C	p.Lys96Asn	missense	Exon 3 of 4	ENSP00000439020.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 90

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	0.11
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	-0.071	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		0.91
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.047	D
Polyphen		0.86	P
Vest4		0.63
MutPred		0.62		Gain of catalytic residue at D98 (P = 0.0027)
MVP		0.85
MPC		3.6
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.94
gMVP		0.98
Mutation Taster		=7/93	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: rs1056875; hg19: chr12-49580180;