chr10-5393537-C-G

Position:

• chr10-5393537-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024803.3(TUBAL3):​c.1321G>C​(p.Glu441Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TUBAL3 NM_024803.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.69

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBAL3	NM_024803.3	c.1321G>C	p.Glu441Gln	missense_variant	4/4	ENST00000380419.8	NP_079079.1
TUBAL3	NM_001171864.2	c.1201G>C	p.Glu401Gln	missense_variant	4/4		NP_001165335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBAL3	ENST00000380419.8	c.1321G>C	p.Glu441Gln	missense_variant	4/4	1	NM_024803.3	ENSP00000369784.3
TUBAL3	ENST00000479328.1	c.1201G>C	p.Glu401Gln	missense_variant	4/4	1		ENSP00000418799.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454558 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 722992

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

May 03, 2023

The c.1321G>C (p.E441Q) alteration is located in exon 4 (coding exon 4) of the TUBAL3 gene. This alteration results from a G to C substitution at nucleotide position 1321, causing the glutamic acid (E) at amino acid position 441 to be replaced by a glutamine (Q). 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	0.23
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.7	L;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.074	T;D
Polyphen		1.0	D;D
Vest4		0.66
MutPred		0.55		Loss of phosphorylation at S445 (P = 0.0947);.;
MVP		0.89
MPC		0.17
ClinPred		0.97	D
GERP RS		4.3
Varity_R		0.38
gMVP		0.22

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-5435500;