12-49185970-G-A

Position:

• chr12-49185970-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006009.4(TUBA1A):​c.396C>T​(p.Leu132Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,614,152 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (1 hom.)
• Consequence: TUBA1A NM_006009.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.46

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052078366).
• BP6: Variant 12-49185970-G-A is Benign according to our data. Variant chr12-49185970-G-A is described in ClinVar as [Benign]. Clinvar id is 160155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49185970-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.46 with no splicing effect.
• BS2: High AC in GnomAd4 at 214 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBA1A	NM_006009.4	c.396C>T	p.Leu132Leu	synonymous_variant	4/4	ENST00000301071.12	NP_006000.2
TUBA1A	NM_001270399.2	c.396C>T	p.Leu132Leu	synonymous_variant	4/4		NP_001257328.1
TUBA1A	NM_001270400.2	c.291C>T	p.Leu97Leu	synonymous_variant	4/4		NP_001257329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBA1A	ENST00000301071.12	c.396C>T	p.Leu132Leu	synonymous_variant	4/4	1	NM_006009.4	ENSP00000301071.7

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152144 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00165 AC: 414 AN: 251410 Hom.: 0 AF XY: 0.00174 AC XY: 237 AN XY: 135892

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00913

Gnomad EAS exome AF: 0.000979

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00173

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00155 AC: 2266 AN: 1461890 Hom.: 1 Cov.: 34 AF XY: 0.00159 AC XY: 1157 AN XY: 727244

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00903

Gnomad4 EAS exome AF: 0.000655

Gnomad4 SAS exome AF: 0.000939

Gnomad4 FIN exome AF: 0.00139

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152262 Hom.: 1 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74442

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00176

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00204 Hom.: 0

Bravo AF: 0.00137

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00162 AC: 197

EpiCase AF: 0.00142

EpiControl AF: 0.00237

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	TUBA1A: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	1.9
DANN	Benign	0.78
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.99	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.052
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.17
MVP		0.57
ClinPred		0.0079	T
GERP RS		-3.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1143560; hg19: chr12-49579753;