2-219251056-G-A

Position:

• chr2-219251056-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2 PP3 BS2

The NM_006000.3(TUBA4A):​c.643C>T​(p.Arg215Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,894 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R215S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TUBA4A NM_006000.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 3.28

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 Likely_benign. Variant got -2 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBA4A. . Gene score misZ 3.3027 (greater than the threshold 3.09). Trascript score misZ 4.9936 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant macrothrombocytopenia, amyotrophic lateral sclerosis type 22.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA4A	NM_006000.3	c.643C>T	p.Arg215Cys	missense_variant	4/4	ENST00000248437.9
TUBA4A	NM_001278552.2	c.598C>T	p.Arg200Cys	missense_variant	4/4
TUBA4A	XM_047445674.1	c.670C>T	p.Arg224Cys	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA4A	ENST00000248437.9	c.643C>T	p.Arg215Cys	missense_variant	4/4	1	NM_006000.3	P1
TUBA4A	ENST00000392088.6	c.598C>T	p.Arg200Cys	missense_variant	4/4	2
TUBA4A	ENST00000398989.2	c.184C>T	p.Arg62Cys	missense_variant	2/2	3
TUBA4A	ENST00000498660.1	n.463C>T		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251496 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727248

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis 22 with frontotemporal dementia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 22, 2014

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2023

Identified in an individual with familial amyotrophic lateral sclerosis with frontotemporal dementia; segregation testing was not performed (Smith BN et al., 2014); Published functional studies found this variant is associated with a small migration difference and altered incorporation into microtubules. However, alpha and beta tubulin dimer assembly was not significantly reduced; the significance of these functional differences is unclear (Smith BN et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37024973, 25374358, 26934450, 27538057, 26780671, 35714755, 33027950, 34169147, 36943622, 36747013) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	28
DANN	Benign	0.91
DEOGEN2	Uncertain	0.64	D;.;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	-0.0020	T
MutationAssessor	Pathogenic	4.9	H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Pathogenic	0.83
Sift4G	Uncertain	0.024	D;D;D
Polyphen		0.036	B;.;.
Vest4		0.89
MutPred		0.55		Gain of catalytic residue at D211 (P = 0.0974);.;.;
MVP		0.79
MPC		1.5
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.91
gMVP		0.88

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: rs730880028; hg19: chr2-220115778;