Genetic Variant TUBA4A:p.Ile437Met (chr2-219250388-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_006000.3(TUBA4A):c.1311C>G(p.Ile437Met) 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. 16/22 in silico tools predict 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. I437I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

TUBA4A
NM_006000.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.280

Publications

0 publications found

Variant links:

Genes affected

TUBA4A (HGNC:12407): (tubulin alpha 4a) Microtubules of the eukaryotic cytoskeleton perform essential and diverse functions and are composed of a heterodimer of alpha and beta tubulin. The genes encoding these microtubule constituents are part of 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 and they are highly conserved among and between species. This gene encodes an alpha tubulin that is a highly conserved homolog of a rat testis-specific alpha tubulin. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2013]

TUBA4A links:

STK16 (HGNC:11394): (serine/threonine kinase 16) Predicted to enable protein serine/threonine kinase activity. Involved in protein autophosphorylation. Located in cytosol; nucleoplasm; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

STK16 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.3027 (above the threshold of 3.09). Trascript score misZ: 4.9936 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant macrothrombocytopenia, amyotrophic lateral sclerosis type 22.

BP4

Computational evidence support a benign effect (MetaRNN=0.13176069).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006000.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TUBA4A	NM_006000.3	MANE Select	c.1311C>G	p.Ile437Met	missense	Exon 4 of 4	NP_005991.1	P68366-1
TUBA4A	NM_001278552.2		c.1266C>G	p.Ile422Met	missense	Exon 4 of 4	NP_001265481.1	P68366-2
STK16	NM_001330213.2	MANE Select	c.*1829G>C		downstream_gene	N/A	NP_001317142.1	O75716

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TUBA4A	ENST00000248437.9	TSL:1 MANE Select	c.1311C>G	p.Ile437Met	missense	Exon 4 of 4	ENSP00000248437.4	P68366-1
TUBA4A	ENST00000875456.1		c.1317C>G	p.Ile439Met	missense	Exon 4 of 4	ENSP00000545515.1
TUBA4A	ENST00000392088.6	TSL:2	c.1266C>G	p.Ile422Met	missense	Exon 4 of 4	ENSP00000375938.2	P68366-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.16

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.017

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.79

MutationAssessor

Benign

-0.70

PhyloP100

0.28

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.10

REVEL

Benign

0.13

Sift4G

Benign

0.28

Polyphen

0.0

Vest4

0.17

MutPred

0.32

Loss of stability (P = 0.1773)

MVP

0.68

MPC

1.0

ClinPred

0.85

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.78

Mutation Taster

=77/23

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over