2-219250652-T-C

Variant names:

• chr2-219250652-T-C
• rs1574883859
• NM_006000.3:c.1047A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_006000.3(TUBA4A):​c.1047A>G​(p.Thr349Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBA4A NM_006000.3 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.38
• Publications: 0 publications found

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]

TUBA4A Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 22

  Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-219250652-T-C is Benign according to our data. Variant chr2-219250652-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3057849.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-2.38 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA4A	NM_006000.3	c.1047A>G	p.Thr349Thr	synonymous_variant	Exon 4 of 4	ENST00000248437.9	NP_005991.1
TUBA4A	NM_001278552.2	c.1002A>G	p.Thr334Thr	synonymous_variant	Exon 4 of 4		NP_001265481.1
TUBA4A	XM_047445674.1	c.1074A>G	p.Thr358Thr	synonymous_variant	Exon 4 of 4		XP_047301630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA4A	ENST00000248437.9	c.1047A>G	p.Thr349Thr	synonymous_variant	Exon 4 of 4	1	NM_006000.3	ENSP00000248437.4
TUBA4A	ENST00000392088.6	c.1002A>G	p.Thr334Thr	synonymous_variant	Exon 4 of 4	2		ENSP00000375938.2
TUBA4A	ENST00000398989.2	c.*120A>G		downstream_gene_variant		3		ENSP00000396212.1
TUBA4A	ENST00000498660.1	n.*77A>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TUBA4A-related disorder Benign:1

Oct 03, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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	-0.82
CADD	Benign	3.2
DANN	Benign	0.61
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1574883859; hg19: chr2-220115374;