chr2-219271517-C-T

Variant names:

• chr2-219271517-C-T
• rs3731891
• NM_001355221.1:c.544C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001355221.1(TUBA4B):​c.544C>T​(p.Arg182Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,614,144 control chromosomes in the GnomAD database, including 860 homozygotes. In-silico tool predicts a benign outcome for this variant. 7/11 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.041 (254 hom., cov: 32)
  • Exomes 𝑓: 0.017 (606 hom.)
• Consequence: TUBA4B NM_001355221.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• Publications: 2 publications found

Genes affected

TUBA4B (HGNC:18637): (tubulin alpha 4b) Predicted to enable GTP binding activity. Predicted to be a structural constituent of cytoskeleton. Predicted to be involved in microtubule cytoskeleton organization and mitotic cell cycle. Predicted to be active in cytoplasm and microtubule. [provided by Alliance of Genome Resources, Apr 2022]

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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068460405).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA4B	NM_001355221.1	c.544C>T	p.Arg182Cys	missense_variant	Exon 4 of 4	ENST00000490341.3	NP_001342150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA4B	ENST00000490341.3	c.544C>T	p.Arg182Cys	missense_variant	Exon 4 of 4	2	NM_001355221.1	ENSP00000487719.1

Frequencies

GnomAD3 genomes AF: 0.0413 AC: 6287 AN: 152146 Hom.: 251 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0256 AC: 6434 AN: 251416 AF XY: 0.0236

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.00862

Gnomad ASJ exome AF: 0.0206

Gnomad EAS exome AF: 0.0981

Gnomad FIN exome AF: 0.0186

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0168 AC: 24539 AN: 1461880 Hom.: 606 Cov.: 68 AF XY: 0.0163 AC XY: 11846 AN XY: 727244

African (AFR) AF: 0.106 AC: 3534 AN: 33478

American (AMR) AF: 0.00941 AC: 421 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0194 AC: 508 AN: 26136

East Asian (EAS) AF: 0.107 AC: 4242 AN: 39700

South Asian (SAS) AF: 0.0121 AC: 1046 AN: 86258

European-Finnish (FIN) AF: 0.0170 AC: 906 AN: 53420

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5768

European-Non Finnish (NFE) AF: 0.0112 AC: 12423 AN: 1112000

Other (OTH) AF: 0.0225 AC: 1361 AN: 60396

GnomAD4 genome AF: 0.0414 AC: 6308 AN: 152264 Hom.: 254 Cov.: 32 AF XY: 0.0415 AC XY: 3089 AN XY: 74446

African (AFR) AF: 0.104 AC: 4316 AN: 41530

American (AMR) AF: 0.0152 AC: 233 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3470

East Asian (EAS) AF: 0.101 AC: 522 AN: 5178

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4830

European-Finnish (FIN) AF: 0.0168 AC: 178 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0126 AC: 856 AN: 68020

Other (OTH) AF: 0.0312 AC: 66 AN: 2114

Alfa AF: 0.0256 Hom.: 21

Bravo AF: 0.0439

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.0104 AC: 40

ExAC AF: 0.0278 AC: 3378

Asia WGS AF: 0.0560 AC: 194 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_noAF	Benign	-0.45
CADD	Benign	23
DANN	Benign	0.86
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0068	T
PhyloP100		1.1
PrimateAI	Uncertain	0.68	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
GERP RS		2.7
Varity_R		0.089
gMVP		0.33

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: rs3731891; hg19: chr2-220136239; COSMIC: COSV67524711;