2-219250700-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006000.3(TUBA4A):c.999C>T(p.Ala333=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000988 in 1,614,202 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00085 (6 hom.)
• Consequence: TUBA4A NM_006000.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.51

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-219250700-G-A is Benign according to our data. Variant chr2-219250700-G-A is described in ClinVar as [Benign]. Clinvar id is 720914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.51 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00227 (346/152312) while in subpopulation AFR AF= 0.00556 (231/41550). AF 95% confidence interval is 0.00497. There are 2 homozygotes in gnomad4. There are 178 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 347 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA4A	NM_006000.3	c.999C>T	p.Ala333=	synonymous_variant	4/4	ENST00000248437.9
TUBA4A	NM_001278552.2	c.954C>T	p.Ala318=	synonymous_variant	4/4
TUBA4A	XM_047445674.1	c.1026C>T	p.Ala342=	synonymous_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA4A	ENST00000248437.9	c.999C>T	p.Ala333=	synonymous_variant	4/4	1	NM_006000.3	P1
TUBA4A	ENST00000392088.6	c.954C>T	p.Ala318=	synonymous_variant	4/4	2
TUBA4A	ENST00000498660.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00228 AC: 347 AN: 152194 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00145 AC: 365 AN: 251480 Hom.: 4 AF XY: 0.00138 AC XY: 187 AN XY: 135916

Gnomad AFR exome AF: 0.00584

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00863

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000800

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.000854 AC: 1249 AN: 1461890 Hom.: 6 Cov.: 31 AF XY: 0.000879 AC XY: 639 AN XY: 727244

Gnomad4 AFR exome AF: 0.00547

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.00781

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000527

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00227 AC: 346 AN: 152312 Hom.: 2 Cov.: 33 AF XY: 0.00239 AC XY: 178 AN XY: 74480

Gnomad4 AFR AF: 0.00556

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00231 Hom.: 2

Bravo AF: 0.00272

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00142

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2019	- -

TUBA4A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	1.1
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs147351423; hg19: chr2-220115422;