rs1056875

chr12-49186397-T-Achr12-49186397-T-Cchr12-49186397-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_006009.4(TUBA1A):c.288A>T(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. In-silico tool predicts a benign outcome for this variant. 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

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TUBA1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.38090998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.288A>T	p.Lys96Asn	missense_variant	3/4	ENST00000301071.12
TUBA1A	NM_001270399.2	c.288A>T	p.Lys96Asn	missense_variant	3/4
TUBA1A	NM_001270400.2	c.183A>T	p.Lys61Asn	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.288A>T	p.Lys96Asn	missense_variant	3/4	1	NM_006009.4	P1
TUBA1B-AS1	ENST00000656133.1	n.474-1886T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 90

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.22	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.25	D
MutationTaster	Benign	0.53	D;D;D;D;D;D;D
PROVEAN	Benign	1.3	N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Vest4		0.27
MutPred		0.39		Loss of ubiquitination at K147 (P = 0.0077);
MVP		0.27
ClinPred		0.99	D
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1056875; hg19: chr12-49580180;