Genetic Variant NM_024803.3:c.944G>A (chr10-5393914-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024803.3(TUBAL3):c.944G>A(p.Arg315Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

TUBAL3
NM_024803.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.19

Variant links:

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]

TUBAL3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12239671).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBAL3	NM_024803.3 link	c.944G>A	p.Arg315Gln	missense_variant	Exon 4 of 4	ENST00000380419.8	NP_079079.1	A6NHL2-1
TUBAL3	NM_001171864.2 link	c.824G>A	p.Arg275Gln	missense_variant	Exon 4 of 4		NP_001165335.1	A6NHL2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBAL3	ENST00000380419.8 link	c.944G>A	p.Arg315Gln	missense_variant	Exon 4 of 4	1	NM_024803.3	ENSP00000369784.3		A6NHL2-1
TUBAL3	ENST00000479328.1 link	c.824G>A	p.Arg275Gln	missense_variant	Exon 4 of 4	1		ENSP00000418799.1		A6NHL2-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251474

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1112012

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.944G>A (p.R315Q) 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 944, causing the arginine (R) at amino acid position 315 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

0.074

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.29

CADD

Benign

4.1

(source)

DANN

Benign

0.91

DEOGEN2

Uncertain

0.64

D;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.85

D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.12

T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Pathogenic

3.1

M;.

PhyloP100

1.2

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-3.0

D;D

REVEL

Uncertain

0.30

Sift

Benign

0.041

D;D

Sift4G

Uncertain

0.056

T;T

Polyphen

0.062

B;B

Vest4

0.13

MVP

0.70

MPC

0.076

ClinPred

0.14

GERP RS

-1.4

Varity_R

0.076

gMVP

0.23

Mutation Taster

=96/4

polymorphism

(source)

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

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NM_024803.3:c.944G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over