2-219250643-C-CTTGAA

Variant names:

• chr2-219250643-C-CTTGAA
• rs1951631864
• NM_006000.3:c.1051_1055dupTTCAA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_006000.3(TUBA4A):​c.1051_1055dupTTCAA​(p.Lys352AsnfsTer29) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBA4A NM_006000.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.99

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_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.217 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-219250643-C-CTTGAA is Pathogenic according to our data. Variant chr2-219250643-C-CTTGAA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 996813.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA4A	NM_006000.3	c.1051_1055dupTTCAA	p.Lys352AsnfsTer29	frameshift_variant	Exon 4 of 4	ENST00000248437.9	NP_005991.1
TUBA4A	NM_001278552.2	c.1006_1010dupTTCAA	p.Lys337AsnfsTer29	frameshift_variant	Exon 4 of 4		NP_001265481.1
TUBA4A	XM_047445674.1	c.1078_1082dupTTCAA	p.Lys361AsnfsTer29	frameshift_variant	Exon 4 of 4		XP_047301630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA4A	ENST00000248437.9	c.1051_1055dupTTCAA	p.Lys352AsnfsTer29	frameshift_variant	Exon 4 of 4	1	NM_006000.3	ENSP00000248437.4
TUBA4A	ENST00000392088.6	c.1006_1010dupTTCAA	p.Lys337AsnfsTer29	frameshift_variant	Exon 4 of 4	2		ENSP00000375938.2
TUBA4A	ENST00000398989.2	c.*124_*128dupTTCAA		downstream_gene_variant		3		ENSP00000396212.1
TUBA4A	ENST00000498660.1	n.*81_*85dupTTCAA		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Feb 01, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1951631864; hg19: chr2-220115365;