NM_006009.4:c.1008G>A

Variant names:

• chr12-49185358-C-T
• rs11829764
• NM_006009.4:c.1008G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_006009.4(TUBA1A):​c.1008G>A​(p.Lys336Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,614,134 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (19 hom.)
• Consequence: TUBA1A NM_006009.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.85
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 12-49185358-C-T is Benign according to our data. Variant chr12-49185358-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 160141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.85 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00792 (1207/152338) while in subpopulation AFR AF = 0.0264 (1099/41562). AF 95% confidence interval is 0.0251. There are 10 homozygotes in GnomAd4. There are 532 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1207 AD gene.

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.1008G>A	p.Lys336Lys	synonymous	Exon 4 of 4	NP_006000.2
	TUBA1A	NM_001270399.2		c.1008G>A	p.Lys336Lys	synonymous	Exon 4 of 4	NP_001257328.1	Q71U36-1
	TUBA1A	NM_001270400.2		c.903G>A	p.Lys301Lys	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.1008G>A	p.Lys336Lys	synonymous	Exon 4 of 4	ENSP00000301071.7	Q71U36-1
	TUBA1A	ENST00000550767.6	TSL:1	c.903G>A	p.Lys301Lys	synonymous	Exon 5 of 5	ENSP00000446637.1	Q71U36-2
	TUBA1A	ENST00000295766.9	TSL:2	c.1008G>A	p.Lys336Lys	synonymous	Exon 4 of 4	ENSP00000439020.2	Q71U36-1

Frequencies

GnomAD3 genomes AF: 0.00786 AC: 1196 AN: 152220 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00205 AC: 514 AN: 250942 AF XY: 0.00146

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.00698

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00108 AC: 1576 AN: 1461796 Hom.: 19 Cov.: 30 AF XY: 0.000916 AC XY: 666 AN XY: 727206

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

African (AFR) AF: 0.0274 AC: 917 AN: 33454

American (AMR) AF: 0.00886 AC: 396 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.0000944 AC: 105 AN: 1111988

Other (OTH) AF: 0.00245 AC: 148 AN: 60390

⚠️ 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: 0.00792 AC: 1207 AN: 152338 Hom.: 10 Cov.: 32 AF XY: 0.00714 AC XY: 532 AN XY: 74494

African (AFR) AF: 0.0264 AC: 1099 AN: 41562

American (AMR) AF: 0.00536 AC: 82 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68038

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00470 Hom.: 1

Bravo AF: 0.00982

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	6.0
DANN	Benign	0.88
PhyloP100		1.9
Mutation Taster		=96/4	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: rs11829764; hg19: chr12-49579141;