NM_006009.4:c.227-38C>G

Variant names:

• chr12-49186496-G-C
• rs112063173
• NM_006009.4:c.227-38C>G

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: -0.0450
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006009.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA1A	NM_006009.4	MANE Select	c.227-38C>G		intron	N/A	NP_006000.2
	TUBA1A	NM_001270399.2		c.227-38C>G		intron	N/A	NP_001257328.1
	TUBA1A	NM_001270400.2		c.122-38C>G		intron	N/A	NP_001257329.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA1A	ENST00000301071.12	TSL:1 MANE Select	c.227-38C>G		intron	N/A	ENSP00000301071.7
	TUBA1A	ENST00000550767.6	TSL:1	c.122-38C>G		intron	N/A	ENSP00000446637.1
	TUBA1A	ENST00000546918.1	TSL:3	c.341C>G	p.Ser114Cys	missense	Exon 2 of 3	ENSP00000446613.1

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

GnomAD2 exomes AF: 0.00535 AC: 1343 AN: 251068 AF XY: 0.00389

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 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

African (AFR) AF: 0.0727 AC: 2420 AN: 33290

American (AMR) AF: 0.00459 AC: 205 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.000464 AC: 40 AN: 86236

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53396

Middle Eastern (MID) AF: 0.00352 AC: 20 AN: 5676

European-Non Finnish (NFE) AF: 0.0000648 AC: 72 AN: 1110914

Other (OTH) AF: 0.00513 AC: 309 AN: 60292

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

African (AFR) AF: 0.0667 AC: 2738 AN: 41066

American (AMR) AF: 0.00781 AC: 119 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67958

Other (OTH) AF: 0.0133 AC: 28 AN: 2106

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
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
PhyloP100		-0.045
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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs112063173; hg19: chr12-49580279;