12-49188874-G-A

Variant names:

• chr12-49188874-G-A
• rs35896524
• NM_006009.4:c.3+103C>T

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.-455C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0482 in 1,612,362 control chromosomes in the GnomAD database, including 2,275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (127 hom., cov: 32)
  • Exomes 𝑓: 0.049 (2148 hom.)
• Consequence: TUBA1A NM_001270399.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.991
• 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]

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=-0.86).
• BP6: Variant 12-49188874-G-A is Benign according to our data. Variant chr12-49188874-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1207784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0531 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+103C>T		intron	N/A	NP_006000.2
	TUBA1A	NM_001270399.2		c.-455C>T		5_prime_UTR	Exon 1 of 4	NP_001257328.1	Q71U36-1
	TUBA1A	NM_001270400.2		c.-103+15C>T		intron	N/A	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+103C>T		intron	N/A	ENSP00000301071.7	Q71U36-1
	TUBA1A	ENST00000550767.6	TSL:1	c.-198+103C>T		intron	N/A	ENSP00000446637.1	Q71U36-2
	TUBA1A	ENST00000295766.9	TSL:2	c.-455C>T		5_prime_UTR	Exon 1 of 4	ENSP00000439020.2	Q71U36-1

Frequencies

GnomAD3 genomes AF: 0.0367 AC: 5576 AN: 152126 Hom.: 127 Cov.: 32

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.0476

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.0440

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0546

Gnomad OTH AF: 0.0444

GnomAD4 exome AF: 0.0495 AC: 72210 AN: 1460118 Hom.: 2148 Cov.: 33 AF XY: 0.0486 AC XY: 35287 AN XY: 726368

African (AFR) AF: 0.00887 AC: 297 AN: 33468

American (AMR) AF: 0.0326 AC: 1460 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 549 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00739 AC: 637 AN: 86252

European-Finnish (FIN) AF: 0.0388 AC: 2012 AN: 51820

Middle Eastern (MID) AF: 0.0369 AC: 213 AN: 5768

European-Non Finnish (NFE) AF: 0.0578 AC: 64289 AN: 1111888

Other (OTH) AF: 0.0456 AC: 2751 AN: 60364

GnomAD4 genome AF: 0.0366 AC: 5574 AN: 152244 Hom.: 127 Cov.: 32 AF XY: 0.0363 AC XY: 2701 AN XY: 74438

African (AFR) AF: 0.0110 AC: 456 AN: 41548

American (AMR) AF: 0.0475 AC: 726 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4824

European-Finnish (FIN) AF: 0.0440 AC: 466 AN: 10600

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0546 AC: 3712 AN: 68016

Other (OTH) AF: 0.0440 AC: 93 AN: 2116

Alfa AF: 0.0367 Hom.: 65

Bravo AF: 0.0366

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely 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	-0.86
CADD	Benign	5.4
DANN	Benign	0.76
PhyloP100		0.99
PromoterAI		-0.038	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35896524; hg19: chr12-49582657;