Genetic Variant TUBA3D:p.Ala12Val (chr2-131478195-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_080386.4(TUBA3D):c.35C>T(p.Ala12Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000434 in 1,613,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

TUBA3D
NM_080386.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.29

Variant links:

Genes affected

TUBA3D (HGNC:24071): (tubulin alpha 3d) This gene encodes a member of the alpha tubulin family. Tubulin is a major component of microtubules, which are composed of alpha- and beta-tubulin heterodimers and microtubule-associated proteins in the cytoskeleton. Microtubules maintain cellular structure, function in intracellular transport, and play a role in spindle formation during mitosis. [provided by RefSeq, Oct 2011]

TUBA3D links:

MZT2A (HGNC:33187): (mitotic spindle organizing protein 2A) Located in centrosome; cytosol; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MZT2A links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.856

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA3D	NM_080386.4 link	c.35C>T	p.Ala12Val	missense_variant	Exon 2 of 5	ENST00000321253.7	NP_525125.2	P0DPH8Q1ZYQ1
MZT2A	XM_047445568.1 link	c.623-6013G>A		intron_variant	Intron 1 of 2		XP_047301524.1
MZT2A	XM_005263742.4 link	c.320-6013G>A		intron_variant	Intron 2 of 3		XP_005263799.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TUBA3D	ENST00000321253.7 link	c.35C>T	p.Ala12Val	missense_variant	Exon 2 of 5	1	NM_080386.4	ENSP00000326042.6	P0DPH8
MZT2A	ENST00000427024.5 link	n.278-6013G>A		intron_variant	Intron 2 of 4	3		ENSP00000403353.1	H7C202
MZT2A	ENST00000445782.2 link	n.331-6013G>A		intron_variant	Intron 2 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000359

AC:

AN:

251036

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000417

AC:

AN:

1461544

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000459

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000849

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35C>T (p.A12V) alteration is located in exon 1 (coding exon 1) of the TUBA3D gene. This alteration results from a C to T substitution at nucleotide position 35, causing the alanine (A) at amino acid position 12 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.0046

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.34

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.79

M_CAP

Benign

0.016

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

-0.018

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.56

Sift4G

Uncertain

0.013

Vest4

0.89

MVP

0.69

ClinPred

0.81

GERP RS

1.6

Varity_R

0.051

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over