rs111590199

Positions:

• chr12-49186500-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006009.4(TUBA1A):​c.227-42T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 148,316 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (61 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (65 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBA1A NM_006009.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.12

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002235651).
• BP6: Variant 12-49186500-A-G is Benign according to our data. Variant chr12-49186500-A-G is described in ClinVar as [Benign]. Clinvar id is 259901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.227-42T>C		intron_variant		ENST00000301071.12
TUBA1A	NM_001270399.2	c.227-42T>C		intron_variant
TUBA1A	NM_001270400.2	c.122-42T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.227-42T>C		intron_variant		1	NM_006009.4	P1
TUBA1B-AS1	ENST00000656133.1	n.474-1783A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2896 AN: 148214 Hom.: 61 Cov.: 31

Gnomad AFR AF: 0.0690

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00822

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000636

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0192

Gnomad NFE AF: 0.000134

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00537 AC: 1346 AN: 250830 Hom.: 28 AF XY: 0.00390 AC XY: 529 AN XY: 135584

Gnomad AFR exome AF: 0.0711

Gnomad AMR exome AF: 0.00443

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000882

Gnomad OTH exome AF: 0.00360

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00210 AC: 3058 AN: 1454134 Hom.: 65 Cov.: 41 AF XY: 0.00183 AC XY: 1324 AN XY: 722052

Gnomad4 AFR exome AF: 0.0726

Gnomad4 AMR exome AF: 0.00469

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000453

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000633

Gnomad4 OTH exome AF: 0.00515

GnomAD4 genome AF: 0.0196 AC: 2913 AN: 148316 Hom.: 61 Cov.: 31 AF XY: 0.0184 AC XY: 1327 AN XY: 72280

Gnomad4 AFR AF: 0.0693

Gnomad4 AMR AF: 0.00821

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000637

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000134

Gnomad4 OTH AF: 0.0127

Alfa AF: 0.0117 Hom.: 6

ESP6500AA AF: 0.0529 AC: 233

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00647 AC: 786

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	2.6
DANN	Benign	0.47
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.050
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.021	D
Vest4		0.16
MVP		0.35
ClinPred		0.029	T
GERP RS		-0.99

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: rs111590199; hg19: chr12-49580283;