Variant 2-131480349-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2

The ENST00000321253.7(TUBA3D):c.656T>C(p.Ile219Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

TUBA3D
ENST00000321253.7 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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

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, 0.84

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TUBA3D	NM_080386.4 linkuse as main transcript	c.656T>C	p.Ile219Thr	missense_variant	4/5	ENST00000321253.7	NP_525125.2
MZT2A	XM_005263742.4 linkuse as main transcript	c.320-8167A>G		intron_variant			XP_005263799.2
MZT2A	XM_047445568.1 linkuse as main transcript	c.623-8167A>G		intron_variant			XP_047301524.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TUBA3D	ENST00000321253.7 linkuse as main transcript	c.656T>C	p.Ile219Thr	missense_variant	4/5	1	NM_080386.4	ENSP00000326042	P1
MZT2A	ENST00000427024.5 linkuse as main transcript	c.279-8167A>G		intron_variant, NMD_transcript_variant		3		ENSP00000403353
MZT2A	ENST00000445782.2 linkuse as main transcript	n.331-8167A>G		intron_variant, non_coding_transcript_variant		2
TUBA3D	ENST00000409047.2 linkuse as main transcript			downstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251246

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461510

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

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

Oct 27, 2022

The c.656T>C (p.I219T) alteration is located in exon 1 (coding exon 1) of the TUBA3D gene. This alteration results from a T to C substitution at nucleotide position 656, causing the isoleucine (I) at amino acid position 219 to be replaced by a threonine (T). 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

-0.0023

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Benign

0.56

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.84

M_CAP

Benign

0.020

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

-0.26

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.52

Sift4G

Benign

0.091

Vest4

0.86

MutPred

0.72

Gain of disorder (P = 0.0187);

MVP

0.47

ClinPred

0.45

GERP RS

2.2

Varity_R

0.074

gMVP

0.55

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