rs61730859

Variant names:

• chr12-49185844-C-T
• rs61730859
• NM_006009.4:c.522G>A

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.522G>A​(p.Ala174Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00694 in 1,610,752 control chromosomes in the GnomAD database, including 332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (150 hom., cov: 31)
  • Exomes 𝑓: 0.0048 (182 hom.)
• Consequence: TUBA1A NM_006009.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.240
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014648736).
• BP6: Variant 12-49185844-C-T is Benign according to our data. Variant chr12-49185844-C-T is described in ClinVar as Benign. ClinVar VariationId is 137850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0841 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.522G>A	p.Ala174Ala	synonymous	Exon 4 of 4	NP_006000.2
	TUBA1A	NM_001270399.2		c.522G>A	p.Ala174Ala	synonymous	Exon 4 of 4	NP_001257328.1	Q71U36-1
	TUBA1A	NM_001270400.2		c.417G>A	p.Ala139Ala	synonymous	Exon 4 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.522G>A	p.Ala174Ala	synonymous	Exon 4 of 4	ENSP00000301071.7	Q71U36-1
	TUBA1A	ENST00000550767.6	TSL:1	c.417G>A	p.Ala139Ala	synonymous	Exon 5 of 5	ENSP00000446637.1	Q71U36-2
	TUBA1A	ENST00000546918.1	TSL:3	c.674G>A	p.Arg225His	missense	Exon 3 of 3	ENSP00000446613.1	F8W0F6

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 4082 AN: 151800 Hom.: 145 Cov.: 31

Gnomad AFR AF: 0.0859

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00387

Gnomad OTH AF: 0.0216

GnomAD2 exomes AF: 0.00830 AC: 2084 AN: 251170 AF XY: 0.00699

Gnomad AFR exome AF: 0.0830

Gnomad AMR exome AF: 0.00385

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00362

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00484 AC: 7065 AN: 1458836 Hom.: 182 Cov.: 30 AF XY: 0.00459 AC XY: 3335 AN XY: 725830

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0826 AC: 2689 AN: 32562

American (AMR) AF: 0.00535 AC: 239 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00444 AC: 116 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00370 AC: 319 AN: 86194

European-Finnish (FIN) AF: 0.000805 AC: 43 AN: 53420

Middle Eastern (MID) AF: 0.00674 AC: 38 AN: 5642

European-Non Finnish (NFE) AF: 0.00288 AC: 3203 AN: 1110240

Other (OTH) AF: 0.00692 AC: 417 AN: 60244

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0271 AC: 4116 AN: 151916 Hom.: 150 Cov.: 31 AF XY: 0.0268 AC XY: 1991 AN XY: 74242

African (AFR) AF: 0.0865 AC: 3577 AN: 41372

American (AMR) AF: 0.0121 AC: 184 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4814

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10576

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.00387 AC: 263 AN: 67976

Other (OTH) AF: 0.0213 AC: 45 AN: 2108

Alfa AF: 0.00917 Hom.: 11

ESP6500AA AF: 0.0749 AC: 330

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.0105 AC: 1275

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	12
DANN	Benign	0.83
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.24
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.080
ClinPred		0.030	T
GERP RS		4.4
Mutation Taster		=58/42	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: rs61730859; hg19: chr12-49579627;