2-219250357-C-T

Variant names:

• chr2-219250357-C-T
• rs1951625882
• NM_006000.3:c.1342G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006000.3(TUBA4A):​c.1342G>A​(p.Glu448Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,456,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TUBA4A NM_006000.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13

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]

STK16 (HGNC:11394): (serine/threonine kinase 16) Predicted to enable protein serine/threonine kinase activity. Involved in protein autophosphorylation. Located in cytosol; nucleoplasm; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41130558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA4A	NM_006000.3	c.1342G>A	p.Glu448Lys	missense_variant	Exon 4 of 4	ENST00000248437.9	NP_005991.1
STK16	NM_001330213.2	c.*1798C>T		downstream_gene_variant		ENST00000396738.7	NP_001317142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA4A	ENST00000248437.9	c.1342G>A	p.Glu448Lys	missense_variant	Exon 4 of 4	1	NM_006000.3	ENSP00000248437.4
TUBA4A	ENST00000392088.6	c.1297G>A	p.Glu433Lys	missense_variant	Exon 4 of 4	2		ENSP00000375938.2
STK16	ENST00000396738.7	c.*1798C>T		downstream_gene_variant		2	NM_001330213.2	ENSP00000379964.2
STK16	ENST00000409638.7	c.*1798C>T		downstream_gene_variant		1		ENSP00000386928.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456186 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723512

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1342G>A (p.E448K) alteration is located in exon 4 (coding exon 4) of the TUBA4A gene. This alteration results from a G to A substitution at nucleotide position 1342, causing the glutamic acid (E) at amino acid position 448 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	0.016
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.73	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.39
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.0	B;.
Vest4		0.58
MutPred		0.28		Gain of ubiquitination at E448 (P = 0.006);.;
MVP		0.79
MPC		1.2
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.62
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs1951625882; hg19: chr2-220115079;