rs111590199

Variant names:

• chr12-49186500-A-G
• rs111590199
• NM_006009.4:c.227-42T>C

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.227-42T>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
• 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=0.002235651).
• BP6: Variant 12-49186500-A-G is Benign according to our data. Variant chr12-49186500-A-G is described in ClinVar as Benign. ClinVar VariationId 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.

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.227-42T>C		intron	N/A	NP_006000.2
	TUBA1A	NM_001270399.2		c.227-42T>C		intron	N/A	NP_001257328.1
	TUBA1A	NM_001270400.2		c.122-42T>C		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.227-42T>C		intron	N/A	ENSP00000301071.7
	TUBA1A	ENST00000550767.6	TSL:1	c.122-42T>C		intron	N/A	ENSP00000446637.1
	TUBA1A	ENST00000546918.1	TSL:3	c.337T>C	p.Ser113Pro	missense	Exon 2 of 3	ENSP00000446613.1

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

GnomAD2 exomes AF: 0.00537 AC: 1346 AN: 250830 AF XY: 0.00390

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 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

African (AFR) AF: 0.0726 AC: 2408 AN: 33190

American (AMR) AF: 0.00469 AC: 209 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.000453 AC: 39 AN: 86106

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53308

Middle Eastern (MID) AF: 0.00335 AC: 19 AN: 5668

European-Non Finnish (NFE) AF: 0.0000633 AC: 70 AN: 1105684

Other (OTH) AF: 0.00515 AC: 309 AN: 59966

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

African (AFR) AF: 0.0693 AC: 2749 AN: 39672

American (AMR) AF: 0.00821 AC: 121 AN: 14732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5062

South Asian (SAS) AF: 0.000637 AC: 3 AN: 4706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10172

Middle Eastern (MID) AF: 0.0172 AC: 5 AN: 290

European-Non Finnish (NFE) AF: 0.000134 AC: 9 AN: 67286

Other (OTH) AF: 0.0127 AC: 26 AN: 2040

Alfa AF: 0.0130 Hom.: 6

ESP6500AA AF: 0.0529 AC: 233

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00647 AC: 786

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
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
PhyloP100		3.1
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
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: rs111590199; hg19: chr12-49580283;