2-131480397-T-A

Position:

chr2-131480397-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_080386.4(TUBA3D):c.704T>A(p.Val235Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,454,740 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 0.0000070 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TUBA3D
NM_080386.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.90

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:

MZT2A (HGNC:):

MZT2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBA3D. . Gene score misZ 1.5331 (greater than the threshold 3.09). Trascript score misZ 3.5821 (greater than threshold 3.09). GenCC has associacion of gene with keratoconus 9.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBA3D	NM_080386.4 linkuse as main transcript	c.704T>A	p.Val235Glu	missense_variant	4/5	ENST00000321253.7	NP_525125.2	P0DPH8Q1ZYQ1
MZT2A	XM_047445568.1 linkuse as main transcript	c.623-8215A>T		intron_variant			XP_047301524.1
MZT2A	XM_005263742.4 linkuse as main transcript	c.320-8215A>T		intron_variant			XP_005263799.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TUBA3D	ENST00000321253.7 linkuse as main transcript	c.704T>A	p.Val235Glu	missense_variant	4/5	1	NM_080386.4	ENSP00000326042.6	P0DPH8
MZT2A	ENST00000427024.5 linkuse as main transcript	n.278-8215A>T		intron_variant		3		ENSP00000403353.1	H7C202
MZT2A	ENST00000445782.2 linkuse as main transcript	n.331-8215A>T		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

143004

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1454740

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723850

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000699

AC:

AN:

143004

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69914

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2024

The c.704T>A (p.V235E) alteration is located in exon 1 (coding exon 1) of the TUBA3D gene. This alteration results from a T to A substitution at nucleotide position 704, causing the valine (V) at amino acid position 235 to be replaced by a glutamic acid (E). 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

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Benign

0.96

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.85

M_CAP

Benign

0.035

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.19

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.64

Sift4G

Pathogenic

0.0010

Vest4

0.95

MutPred

0.61

Gain of disorder (P = 0.0349);

MVP

0.60

ClinPred

0.99

GERP RS

2.2

Varity_R

0.23

gMVP

0.89

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

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