12-49186784-T-C

Variant names:

• chr12-49186784-T-C
• rs1064795213
• NM_006009.4:c.53A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PM1 PM2 PM5 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N18Y) has been classified as Likely pathogenic.

• 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
• Publications: 3 publications found

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]

TUBA1B-AS1 (HGNC:56356): (TUBA1B antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_006009.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-49186785-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3024266.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the TUBA1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 163 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. Gene score misZ: 5.584 (above the threshold of 3.09). Trascript score misZ: 8.7455 (above the threshold of 3.09). GenCC associations: The gene is linked to lissencephaly due to TUBA1A mutation, tubulinopathy-associated dysgyria, tubulinopathy.
• 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 VariationId is 421567.
• BP4: Computational evidence support a benign effect (MetaRNN=0.35648954). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006009.4. 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
	TUBA1A	NM_006009.4	MANE Select	c.53A>G	p.Asn18Ser	missense	Exon 2 of 4	NP_006000.2
	TUBA1A	NM_001270399.2		c.53A>G	p.Asn18Ser	missense	Exon 2 of 4	NP_001257328.1	Q71U36-1
	TUBA1A	NM_001270400.2		c.-53A>G		5_prime_UTR	Exon 2 of 4	NP_001257329.1	Q71U36-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA1A	ENST00000301071.12	TSL:1 MANE Select	c.53A>G	p.Asn18Ser	missense	Exon 2 of 4	ENSP00000301071.7	Q71U36-1
	TUBA1A	ENST00000550767.6	TSL:1	c.-53A>G		5_prime_UTR	Exon 3 of 5	ENSP00000446637.1	Q71U36-2
	TUBA1A	ENST00000295766.9	TSL:2	c.53A>G	p.Asn18Ser	missense	Exon 2 of 4	ENSP00000439020.2	Q71U36-1

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

⚠️ 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: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)
1	-	-	Lissencephaly due to TUBA1A mutation (1)
-	1	-	not specified (1)
1	-	-	Tubulinopathy (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.10	T
Polyphen		0.0070	B
Vest4		0.45
MutPred		0.65		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
Mutation Taster		=8/92	disease causing (ClinVar)

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: rs1064795213; hg19: chr12-49580567;