chr2-219253950-CGGGGG-C

Variant names:

• chr2-219253948-GGCGGG-GGC
• NM_001355221.1:c.12+539_12+541delGGG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001355221.1(TUBA4B):​c.12+539_12+541delGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBA4B NM_001355221.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.536
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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+539_12+541delGGG		intron	N/A	NP_001342150.1	Q9H853
	TUBA4A	NM_001278552.2		c.-43+142_-43+144delCCC		intron	N/A	NP_001265481.1	P68366-2
	TUBA4A	NM_006000.3	MANE Select	c.-95_-93delCCC		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+532_12+534delGGG		intron	N/A	ENSP00000487719.1	Q9H853
	TUBA4B	ENST00000473885.5	TSL:1	n.177+532_177+534delGGG		intron	N/A
	TUBA4B	ENST00000485041.5	TSL:1	n.177+532_177+534delGGG		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 382860 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 186730

African (AFR) AF: 0.00 AC: 0 AN: 11792

American (AMR) AF: 0.00 AC: 0 AN: 5398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7454

East Asian (EAS) AF: 0.00 AC: 0 AN: 17654

South Asian (SAS) AF: 0.00 AC: 0 AN: 9512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1324

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 288312

Other (OTH) AF: 0.00 AC: 0 AN: 17896

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.54

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-220118670;