2-219250357-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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

Scores

1
6
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.13
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
TUBA4ANM_006000.3 linkc.1342G>A p.Glu448Lys missense_variant Exon 4 of 4 ENST00000248437.9 NP_005991.1 P68366-1
STK16NM_001330213.2 linkc.*1798C>T downstream_gene_variant ENST00000396738.7 NP_001317142.1 O75716

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TUBA4AENST00000248437.9 linkc.1342G>A p.Glu448Lys missense_variant Exon 4 of 4 1 NM_006000.3 ENSP00000248437.4 P68366-1
TUBA4AENST00000392088.6 linkc.1297G>A p.Glu433Lys missense_variant Exon 4 of 4 2 ENSP00000375938.2 P68366-2
STK16ENST00000396738.7 linkc.*1798C>T downstream_gene_variant 2 NM_001330213.2 ENSP00000379964.2 O75716
STK16ENST00000409638.7 linkc.*1798C>T downstream_gene_variant 1 ENSP00000386928.3 O75716

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
show subpopulations
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
LINK: link

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1951625882; hg19: chr2-220115079; API