rs199717430

Positions:

• chr12-49186601-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006009.4(TUBA1A):​c.226+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 1,613,994 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00084 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (14 hom.)
• Consequence: TUBA1A NM_006009.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.747

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005897194).
• BP6: Variant 12-49186601-G-A is Benign according to our data. Variant chr12-49186601-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 160152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49186601-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000709 (1037/1461718) while in subpopulation MID AF= 0.0347 (200/5768). AF 95% confidence interval is 0.0307. There are 14 homozygotes in gnomad4_exome. There are 534 alleles in male gnomad4_exome subpopulation. Median coverage is 38. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 128 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBA1A	NM_006009.4	c.226+10C>T		intron_variant		ENST00000301071.12	NP_006000.2
TUBA1A	NM_001270399.2	c.226+10C>T		intron_variant			NP_001257328.1
TUBA1A	NM_001270400.2	c.121+10C>T		intron_variant			NP_001257329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBA1A	ENST00000301071.12	c.226+10C>T		intron_variant		1	NM_006009.4	ENSP00000301071.7

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000887 AC: 223 AN: 251358 Hom.: 0 AF XY: 0.000942 AC XY: 128 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.00379

Gnomad NFE exome AF: 0.000800

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.000709 AC: 1037 AN: 1461718 Hom.: 14 Cov.: 38 AF XY: 0.000734 AC XY: 534 AN XY: 727158

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.00367

Gnomad4 NFE exome AF: 0.000430

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.000841 AC: 128 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.000994 AC XY: 74 AN XY: 74452

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00100 Hom.: 0

Bravo AF: 0.000555

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000708 AC: 86

EpiCase AF: 0.00104

EpiControl AF: 0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	TUBA1A: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 23, 2015

- -

TUBA1A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.90
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.71	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.055
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.058	T
Vest4		0.12
MVP		0.56
ClinPred		0.031	T
GERP RS		3.0

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: rs199717430; hg19: chr12-49580384;