chr10-5393540-C-T

Variant names:

• chr10-5393540-C-T
• rs1035889424
• NM_024803.3:c.1318G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E440V) has been classified 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024803.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBAL3	NM_024803.3	MANE Select	c.1318G>A	p.Glu440Lys	missense	Exon 4 of 4	NP_079079.1	A6NHL2-1
	TUBAL3	NM_001171864.2		c.1198G>A	p.Glu400Lys	missense	Exon 4 of 4	NP_001165335.1	A6NHL2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBAL3	ENST00000380419.8	TSL:1 MANE Select	c.1318G>A	p.Glu440Lys	missense	Exon 4 of 4	ENSP00000369784.3	A6NHL2-1
	TUBAL3	ENST00000479328.1	TSL:1	c.1198G>A	p.Glu400Lys	missense	Exon 4 of 4	ENSP00000418799.1	A6NHL2-2

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 44360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25734

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 85642

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110404

Other (OTH) AF: 0.0000166 AC: 1 AN: 60230

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0132501), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.13	T
Polyphen		0.0080	B
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
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

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