2-219253950-CGGGGGG-CGGGGG

Variant names:

• chr2-219253950-CG-C
• rs3051654
• NM_001355221.1:c.12+541delG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001355221.1(TUBA4B):​c.12+541delG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0969 in 464,262 control chromosomes in the GnomAD database, including 1,644 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.087 (940 hom., cov: 30)
  • Exomes 𝑓: 0.10 (704 hom.)
• Consequence: TUBA4B NM_001355221.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.431
• Publications: 0 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 2-219253950-CG-C is Benign according to our data. Variant chr2-219253950-CG-C is described in ClinVar as Benign. ClinVar VariationId is 1241194.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001355221.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA4B	NM_001355221.1	MANE Select	c.12+541delG		intron	N/A	NP_001342150.1	Q9H853
	TUBA4A	NM_001278552.2		c.-43+144delC		intron	N/A	NP_001265481.1	P68366-2
	TUBA4A	NM_006000.3	MANE Select	c.-93delC		upstream_gene	N/A	NP_005991.1	P68366-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA4B	ENST00000490341.3	TSL:2 MANE Select	c.12+532delG		intron	N/A	ENSP00000487719.1	Q9H853
	TUBA4B	ENST00000473885.5	TSL:1	n.177+532delG		intron	N/A
	TUBA4B	ENST00000485041.5	TSL:1	n.177+532delG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0870 AC: 10982 AN: 126276 Hom.: 937 Cov.: 30

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.0107

Gnomad AMR AF: 0.0337

Gnomad ASJ AF: 0.0258

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.0262

Gnomad FIN AF: 0.0334

Gnomad MID AF: 0.0420

Gnomad NFE AF: 0.0178

Gnomad OTH AF: 0.0771

GnomAD4 exome AF: 0.101 AC: 33980 AN: 337928 Hom.: 704 Cov.: 12 AF XY: 0.0971 AC XY: 15992 AN XY: 164638

African (AFR) AF: 0.357 AC: 4010 AN: 11224

American (AMR) AF: 0.0838 AC: 396 AN: 4726

Ashkenazi Jewish (ASJ) AF: 0.0728 AC: 467 AN: 6418

East Asian (EAS) AF: 0.189 AC: 3010 AN: 15934

South Asian (SAS) AF: 0.123 AC: 1020 AN: 8296

European-Finnish (FIN) AF: 0.0638 AC: 1339 AN: 20996

Middle Eastern (MID) AF: 0.0785 AC: 93 AN: 1184

European-Non Finnish (NFE) AF: 0.0864 AC: 21889 AN: 253372

Other (OTH) AF: 0.111 AC: 1756 AN: 15778

GnomAD4 genome AF: 0.0871 AC: 11010 AN: 126334 Hom.: 940 Cov.: 30 AF XY: 0.0861 AC XY: 5289 AN XY: 61412

African (AFR) AF: 0.233 AC: 8454 AN: 36254

American (AMR) AF: 0.0337 AC: 429 AN: 12730

Ashkenazi Jewish (ASJ) AF: 0.0258 AC: 75 AN: 2904

East Asian (EAS) AF: 0.130 AC: 540 AN: 4162

South Asian (SAS) AF: 0.0260 AC: 96 AN: 3696

European-Finnish (FIN) AF: 0.0334 AC: 271 AN: 8108

Middle Eastern (MID) AF: 0.0364 AC: 8 AN: 220

European-Non Finnish (NFE) AF: 0.0179 AC: 996 AN: 55796

Other (OTH) AF: 0.0775 AC: 133 AN: 1716

Alfa AF: 0.0120 Hom.: 7

Bravo AF: 0.0824

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.43
Mutation Taster		=300/0	polymorphism (auto)

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: rs3051654; hg19: chr2-220118672; COSMIC: COSV107215429; COSMIC: COSV107215429;