12-49185102-G-T

Variant names:

• chr12-49185102-G-T
• rs137853049
• NM_006009.4:c.1264C>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_006009.4(TUBA1A):​c.1264C>A​(p.Arg422Ser) variant causes a missense change. 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R422H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TUBA1A NM_006009.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.84
• Publications: 0 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 11 ACMG points.

• PM1: In a hotspot region, there are 6 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-49185101-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 7077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.897
• PP5: Variant 12-49185102-G-T is Pathogenic according to our data. Variant chr12-49185102-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1330377.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA1A	NM_006009.4	c.1264C>A	p.Arg422Ser	missense_variant	Exon 4 of 4	ENST00000301071.12	NP_006000.2
TUBA1A	NM_001270399.2	c.1264C>A	p.Arg422Ser	missense_variant	Exon 4 of 4		NP_001257328.1
TUBA1A	NM_001270400.2	c.1159C>A	p.Arg387Ser	missense_variant	Exon 4 of 4		NP_001257329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA1A	ENST00000301071.12	c.1264C>A	p.Arg422Ser	missense_variant	Exon 4 of 4	1	NM_006009.4	ENSP00000301071.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tubulinopathy-associated dysgyria Pathogenic:1

Nov 01, 2021

Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.57	D;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	.;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.9	H;H;.
PhyloP100		5.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.044	D;D;D
Polyphen		0.96	D;D;.
Vest4		0.72
MutPred		0.68		Gain of phosphorylation at R422 (P = 0.0109);Gain of phosphorylation at R422 (P = 0.0109);.;
MVP		0.92
MPC		3.7
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.99
Mutation Taster		=8/92	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: rs137853049; hg19: chr12-49578885; COSMIC: COSV55498246; COSMIC: COSV55498246;