Genetic Variant TUBA3D:p.Arg214Trp (chr2-131480333-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_080386.4(TUBA3D):c.640C>T(p.Arg214Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 150,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000015 ( 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: 3.13

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18843499).

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA3D	NM_080386.4 link	c.640C>T	p.Arg214Trp	missense_variant	Exon 4 of 5	ENST00000321253.7	NP_525125.2	P0DPH8Q1ZYQ1
MZT2A	XM_047445568.1 link	c.623-8151G>A		intron_variant	Intron 1 of 2		XP_047301524.1
MZT2A	XM_005263742.4 link	c.320-8151G>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.640C>T	p.Arg214Trp	missense_variant	Exon 4 of 5	1	NM_080386.4	ENSP00000326042.6	P0DPH8
TUBA3D	ENST00000409047.2 link	n.466C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2
MZT2A	ENST00000427024.5 link	n.278-8151G>A		intron_variant	Intron 2 of 4	3		ENSP00000403353.1	H7C202
MZT2A	ENST00000445782.2 link	n.331-8151G>A		intron_variant	Intron 2 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0000465

AC:

AN:

150626

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000749

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:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251082

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000151

AC:

AN:

1461362

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000465

AC:

AN:

150626

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73546

show subpopulations

Gnomad4 AFR

AF:

0.0000749

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000148

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.640C>T (p.R214W) 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 640, causing the arginine (R) at amino acid position 214 to be replaced by a tryptophan (W). 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

-0.024

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Benign

0.97

Eigen

Benign

-0.021

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.57

M_CAP

Benign

0.0091

MetaRNN

Benign

0.19

MetaSVM

Uncertain

-0.21

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.40

Sift4G

Uncertain

0.021

Vest4

0.38

MVP

0.43

ClinPred

0.82

GERP RS

1.3

Varity_R

0.14

gMVP

0.65

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