10-5393540-C-T

Position:

• chr10-5393540-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024803.3(TUBAL3):​c.1318G>A​(p.Glu440Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,458,398 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TUBAL3 NM_024803.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.85

Genes affected

TUBAL3 (HGNC:23534): (tubulin alpha like 3) 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBAL3	NM_024803.3	c.1318G>A	p.Glu440Lys	missense_variant	4/4	ENST00000380419.8	NP_079079.1
TUBAL3	NM_001171864.2	c.1198G>A	p.Glu400Lys	missense_variant	4/4		NP_001165335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBAL3	ENST00000380419.8	c.1318G>A	p.Glu440Lys	missense_variant	4/4	1	NM_024803.3	ENSP00000369784	P1
TUBAL3	ENST00000479328.1	c.1198G>A	p.Glu400Lys	missense_variant	4/4	1		ENSP00000418799

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458398 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725210

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: 0.0000188

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 16, 2024

The c.1318G>A (p.E440K) alteration is located in exon 4 (coding exon 4) of the TUBAL3 gene. This alteration results from a G to A substitution at nucleotide position 1318, causing the glutamic acid (E) at amino acid position 440 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	0.084
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	0.91	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.13	T;T
Polyphen		0.0080	B;P
Vest4		0.61
MutPred		0.42		Gain of methylation at E440 (P = 0.0092);.;
MVP		0.80
MPC		0.13
ClinPred		0.86	D
GERP RS		1.4
Varity_R		0.13
gMVP		0.29

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: rs1035889424; hg19: chr10-5435503; COSMIC: COSV100990446;