rs112063173

chr12-49186496-G-C

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.227-38C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 151,590 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (58 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:2
• Conservation: PhyloP100: -0.0450

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=0.0029357076).
• BP6: Variant 12-49186496-G-C is Benign according to our data. Variant chr12-49186496-G-C is described in ClinVar as [Benign]. Clinvar id is 259900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.227-38C>G		intron_variant		ENST00000301071.12
TUBA1A	NM_001270399.2	c.227-38C>G		intron_variant
TUBA1A	NM_001270400.2	c.122-38C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.227-38C>G		intron_variant		1	NM_006009.4	P1
TUBA1B-AS1	ENST00000656133.1	n.474-1787G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2885 AN: 151474 Hom.: 58 Cov.: 31

Gnomad AFR AF: 0.0664

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00782

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00535 AC: 1343 AN: 251068 Hom.: 28 AF XY: 0.00389 AC XY: 528 AN XY: 135712

Gnomad AFR exome AF: 0.0710

Gnomad AMR exome AF: 0.00443

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000881

Gnomad OTH exome AF: 0.00359

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00210 AC: 3070 AN: 1460286 Hom.: 65 Cov.: 41 AF XY: 0.00183 AC XY: 1327 AN XY: 726198

Gnomad4 AFR exome AF: 0.0727

Gnomad4 AMR exome AF: 0.00459

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000648

Gnomad4 OTH exome AF: 0.00513

GnomAD4 genome AF: 0.0191 AC: 2902 AN: 151590 Hom.: 58 Cov.: 31 AF XY: 0.0179 AC XY: 1323 AN XY: 74106

Gnomad4 AFR AF: 0.0667

Gnomad4 AMR AF: 0.00781

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.0114 Hom.: 6

ESP6500AA AF: 0.0606 AC: 267

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00647 AC: 786

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 13, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	0.64
Dann	Benign	0.58
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.066
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Vest4		0.26
MVP		0.33
ClinPred		0.0047	T
GERP RS		-4.3

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: rs112063173; hg19: chr12-49580279;