rs1135224

chr12-49185988-G-Achr12-49185988-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_006009.4(TUBA1A):c.378C>T(p.Ala126=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,613,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A126A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: TUBA1A NM_006009.4 splice_region, synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.842

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14813825).
• BP6: Variant 12-49185988-G-A is Benign according to our data. Variant chr12-49185988-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 437117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49185988-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.378C>T	p.Ala126=	splice_region_variant, synonymous_variant	4/4	ENST00000301071.12
TUBA1A	NM_001270399.2	c.378C>T	p.Ala126=	splice_region_variant, synonymous_variant	4/4
TUBA1A	NM_001270400.2	c.273C>T	p.Ala91=	splice_region_variant, synonymous_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.378C>T	p.Ala126=	splice_region_variant, synonymous_variant	4/4	1	NM_006009.4	P1
TUBA1B-AS1	ENST00000656133.1	n.474-2295G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

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: 0.000176

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000876 AC: 22 AN: 251056 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000133 AC: 195 AN: 1461872 Hom.: 0 Cov.: 34 AF XY: 0.000142 AC XY: 103 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000156

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000132 AC: 20 AN: 151990 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74232

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000907

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 07, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	3.7
Dann	Benign	0.74
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.30
Sift	Benign	0.22	T
Sift4G	Benign	1.0	T
Vest4		0.14
MVP		0.70
ClinPred		0.025	T
GERP RS		-4.1

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: rs1135224; hg19: chr12-49579771;