NM_006009.4:c.453G>C

Variant names:

• chr12-49185913-C-G
• rs697624
• NM_006009.4:c.453G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006009.4(TUBA1A):​c.453G>C​(p.Ser151Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 1,612,662 control chromosomes in the GnomAD database, including 126,002 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S151S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.45 (17126 hom., cov: 30)
  • Exomes 𝑓: 0.38 (108876 hom.)
• Consequence: TUBA1A NM_006009.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.300
• Publications: 24 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1844239E-5).
• BP6: Variant 12-49185913-C-G is Benign according to our data. Variant chr12-49185913-C-G is described in ClinVar as Benign. ClinVar VariationId is 160157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.701 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA1A	NM_006009.4	MANE Select	c.453G>C	p.Ser151Ser	synonymous	Exon 4 of 4	NP_006000.2
	TUBA1A	NM_001270399.2		c.453G>C	p.Ser151Ser	synonymous	Exon 4 of 4	NP_001257328.1
	TUBA1A	NM_001270400.2		c.348G>C	p.Ser116Ser	synonymous	Exon 4 of 4	NP_001257329.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA1A	ENST00000301071.12	TSL:1 MANE Select	c.453G>C	p.Ser151Ser	synonymous	Exon 4 of 4	ENSP00000301071.7
	TUBA1A	ENST00000550767.6	TSL:1	c.348G>C	p.Ser116Ser	synonymous	Exon 5 of 5	ENSP00000446637.1
	TUBA1A	ENST00000546918.1	TSL:3	c.605G>C	p.Arg202Pro	missense	Exon 3 of 3	ENSP00000446613.1

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68608 AN: 151586 Hom.: 17079 Cov.: 30

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.223

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.345

Gnomad OTH AF: 0.417

GnomAD2 exomes AF: 0.416 AC: 104302 AN: 250668 AF XY: 0.416

Gnomad AFR exome AF: 0.649

Gnomad AMR exome AF: 0.349

Gnomad ASJ exome AF: 0.268

Gnomad EAS exome AF: 0.736

Gnomad FIN exome AF: 0.403

Gnomad NFE exome AF: 0.341

Gnomad OTH exome AF: 0.382

GnomAD4 exome AF: 0.377 AC: 550350 AN: 1460954 Hom.: 108876 Cov.: 76 AF XY: 0.379 AC XY: 275721 AN XY: 726792

African (AFR) AF: 0.655 AC: 21858 AN: 33384

American (AMR) AF: 0.353 AC: 15732 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 7172 AN: 26114

East Asian (EAS) AF: 0.715 AC: 28359 AN: 39664

South Asian (SAS) AF: 0.520 AC: 44836 AN: 86232

European-Finnish (FIN) AF: 0.404 AC: 21585 AN: 53382

Middle Eastern (MID) AF: 0.270 AC: 1557 AN: 5768

European-Non Finnish (NFE) AF: 0.347 AC: 385537 AN: 1111472

Other (OTH) AF: 0.393 AC: 23714 AN: 60360

GnomAD4 genome AF: 0.453 AC: 68717 AN: 151708 Hom.: 17126 Cov.: 30 AF XY: 0.457 AC XY: 33894 AN XY: 74092

African (AFR) AF: 0.648 AC: 26807 AN: 41344

American (AMR) AF: 0.376 AC: 5727 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 932 AN: 3468

East Asian (EAS) AF: 0.721 AC: 3695 AN: 5126

South Asian (SAS) AF: 0.550 AC: 2645 AN: 4812

European-Finnish (FIN) AF: 0.412 AC: 4332 AN: 10522

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.345 AC: 23421 AN: 67904

Other (OTH) AF: 0.417 AC: 876 AN: 2100

Alfa AF: 0.317 Hom.: 2394

Bravo AF: 0.454

TwinsUK AF: 0.336 AC: 1245

ALSPAC AF: 0.358 AC: 1379

ESP6500AA AF: 0.642 AC: 2830

ESP6500EA AF: 0.329 AC: 2826

ExAC AF: 0.421 AC: 51082

EpiCase AF: 0.337

EpiControl AF: 0.328

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Lissencephaly due to TUBA1A mutation (1)
-	-	1	TUBA1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	7.4
DANN	Benign	0.71
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.000012	T
MetaSVM	Benign	-0.95	T
PhyloP100		0.30
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.044
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.32	T
Vest4		0.081
ClinPred		0.011	T
GERP RS		0.17
Mutation Taster		=94/6	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: rs697624; hg19: chr12-49579696; COSMIC: COSV55496973; COSMIC: COSV55496973;