chr2-219251056-G-A

Variant names:

• chr2-219251056-G-A
• rs730880028
• NM_006000.3:c.643C>T

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 8 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 -2 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.3027 (above the threshold of 3.09). Trascript score misZ: 4.9936 (above the threshold of 3.09). GenCC associations: The gene is linked to 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,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006000.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA4A	NM_006000.3	MANE Select	c.643C>T	p.Arg215Cys	missense	Exon 4 of 4	NP_005991.1
	TUBA4A	NM_001278552.2		c.598C>T	p.Arg200Cys	missense	Exon 4 of 4	NP_001265481.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA4A	ENST00000248437.9	TSL:1 MANE Select	c.643C>T	p.Arg215Cys	missense	Exon 4 of 4	ENSP00000248437.4
	TUBA4A	ENST00000392088.6	TSL:2	c.598C>T	p.Arg200Cys	missense	Exon 4 of 4	ENSP00000375938.2
	TUBA4A	ENST00000398989.2	TSL:3	c.184C>T	p.Arg62Cys	missense	Exon 2 of 2	ENSP00000396212.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251496 AF XY: 0.00000736

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Amyotrophic lateral sclerosis type 22 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.0020	T
MutationAssessor	Pathogenic	4.9	H
PhyloP100		3.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.83
Sift4G	Uncertain	0.024	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
Mutation Taster		=20/80	disease causing (ClinVar)

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: rs730880028; hg19: chr2-220115778;