12-49188909-T-G

Variant names:

• chr12-49188909-T-G
• rs1039225
• NM_006009.4:c.3+68A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001270399.2(TUBA1A):​c.-490A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,613,412 control chromosomes in the GnomAD database, including 103,113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8565 hom., cov: 32)
  • Exomes 𝑓: 0.35 (94548 hom.)
• Consequence: TUBA1A NM_001270399.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.20
• Publications: 22 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]

TUBA1C (HGNC:20768): (tubulin alpha 1c) Predicted to enable GTP binding activity. Predicted to be a structural constituent of cytoskeleton. Predicted to be involved in microtubule cytoskeleton organization and mitotic cell cycle. Located in microtubule cytoskeleton and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-49188909-T-G is Benign according to our data. Variant chr12-49188909-T-G is described in ClinVar as Benign. ClinVar VariationId is 1238419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270399.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA1A	NM_006009.4	MANE Select	c.3+68A>C		intron	N/A	NP_006000.2
	TUBA1A	NM_001270399.2		c.-490A>C		5_prime_UTR	Exon 1 of 4	NP_001257328.1	Q71U36-1
	TUBA1A	NM_001270400.2		c.-123A>C		5_prime_UTR	Exon 1 of 4	NP_001257329.1	Q71U36-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA1A	ENST00000301071.12	TSL:1 MANE Select	c.3+68A>C		intron	N/A	ENSP00000301071.7	Q71U36-1
	TUBA1A	ENST00000550767.6	TSL:1	c.-198+68A>C		intron	N/A	ENSP00000446637.1	Q71U36-2
	TUBA1A	ENST00000552924.2	TSL:2	c.-123A>C		5_prime_UTR	Exon 1 of 4	ENSP00000448725.2	Q71U36-2

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48569 AN: 151690 Hom.: 8563 Cov.: 32

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.311

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.715

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.308

GnomAD4 exome AF: 0.350 AC: 512081 AN: 1461604 Hom.: 94548 Cov.: 56 AF XY: 0.353 AC XY: 256967 AN XY: 727096

African (AFR) AF: 0.211 AC: 7080 AN: 33480

American (AMR) AF: 0.319 AC: 14265 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 6319 AN: 26136

East Asian (EAS) AF: 0.714 AC: 28361 AN: 39700

South Asian (SAS) AF: 0.472 AC: 40685 AN: 86258

European-Finnish (FIN) AF: 0.403 AC: 21404 AN: 53156

Middle Eastern (MID) AF: 0.214 AC: 1236 AN: 5768

European-Non Finnish (NFE) AF: 0.334 AC: 371538 AN: 1111992

Other (OTH) AF: 0.351 AC: 21193 AN: 60390

GnomAD4 genome AF: 0.320 AC: 48586 AN: 151808 Hom.: 8565 Cov.: 32 AF XY: 0.328 AC XY: 24339 AN XY: 74176

African (AFR) AF: 0.223 AC: 9231 AN: 41356

American (AMR) AF: 0.311 AC: 4750 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 812 AN: 3468

East Asian (EAS) AF: 0.715 AC: 3685 AN: 5152

South Asian (SAS) AF: 0.505 AC: 2436 AN: 4820

European-Finnish (FIN) AF: 0.409 AC: 4315 AN: 10540

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.331 AC: 22458 AN: 67904

Other (OTH) AF: 0.306 AC: 646 AN: 2108

Alfa AF: 0.320 Hom.: 12851

Bravo AF: 0.305

Asia WGS AF: 0.557 AC: 1934 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.4
DANN	Benign	0.55
PhyloP100		-1.2
PromoterAI		-0.028	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs1039225; hg19: chr12-49582692;