12-49186784-T-C

Position:

• chr12-49186784-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PP2 PP5 BP4

The NM_006009.4(TUBA1A):​c.53A>G​(p.Asn18Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,890 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TUBA1A NM_006009.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 6.17

Genes affected

TUBA1A (HGNC:20766): (tubulin alpha 1a) Microtubules of the eukaryotic cytoskeleton perform essential and diverse functions and are composed of a heterodimer of alpha and beta tubulins. The genes encoding these microtubule constituents belong to 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, which are highly conserved among species. This gene encodes alpha tubulin and is highly similar to the mouse and rat Tuba1 genes. Northern blot studies have shown that the gene expression is predominantly found in morphologically differentiated neurologic cells. This gene is one of three alpha-tubulin genes in a cluster on chromosome 12q. Mutations in this gene cause lissencephaly type 3 (LIS3) - a neurological condition characterized by microcephaly, intellectual disability, and early-onset epilepsy caused by defective neuronal migration. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

TUBA1A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a helix (size 15) in uniprot entity TBA1A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_006009.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBA1A. . Gene score misZ 5.584 (greater than the threshold 3.09). Trascript score misZ 8.7455 (greater than threshold 3.09). GenCC has associacion of gene with tubulinopathy-associated dysgyria, intellectual disability, autosomal dominant 40, tubulinopathy, lissencephaly due to TUBA1A mutation.
• PP5: Variant 12-49186784-T-C is Pathogenic according to our data. Variant chr12-49186784-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421567.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2, Likely_pathogenic=1}. Variant chr12-49186784-T-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.35648954). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBA1A	NM_006009.4	c.53A>G	p.Asn18Ser	missense_variant	2/4	ENST00000301071.12	NP_006000.2
TUBA1A	NM_001270399.2	c.53A>G	p.Asn18Ser	missense_variant	2/4		NP_001257328.1
TUBA1A	NM_001270400.2	c.-53A>G		5_prime_UTR_variant	2/4		NP_001257329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBA1A	ENST00000301071.12	c.53A>G	p.Asn18Ser	missense_variant	2/4	1	NM_006009.4	ENSP00000301071.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 727248

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 13, 2022	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 18 of the TUBA1A protein (p.Asn18Ser). This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Asn18 amino acid residue in TUBA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TUBA1A protein function. ClinVar contains an entry for this variant (Variation ID: 421567). This missense change has been observed in individual(s) with TUBA1A-related conditions (PMID: 28973083). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2023	Identified in presumably affected individuals in the published literature, but familial segregation information and clinical information were not included (Hebebrand et al., 2019; Meng et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 30744660, 28973083) -

Lissencephaly due to TUBA1A mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Medicine Lab, University of California San Francisco

Feb 18, 2021

- -

Tubulinopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

literature only

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Jul 01, 2018

A variant that is classified as likely pathogenic has been identified in the TUBA1A gene in a born individual of unknown sex. The c.53A>G, p.(Asn18Ser) variant has been reported as a variant of germline/unknown origin. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 18, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;T;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	.;T;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.8	L;L;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.10	T;T;D
Polyphen		0.0070	B;B;.
Vest4		0.45
MutPred		0.65		Gain of catalytic residue at N18 (P = 0);Gain of catalytic residue at N18 (P = 0);Gain of catalytic residue at N18 (P = 0);
MVP		0.74
MPC		1.8
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.77
gMVP		0.95

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: rs1064795213; hg19: chr12-49580567;