12-49185580-A-G

Variant names:

• chr12-49185580-A-G
• rs762008241
• NM_006009.4:c.786T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006009.4(TUBA1A):​c.786T>C​(p.Tyr262Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0009 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00035 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBA1A NM_006009.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.396
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 12-49185580-A-G is Benign according to our data. Variant chr12-49185580-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.396 with no splicing effect.
• BS2: High AC in GnomAd4 at 137 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA1A	NM_006009.4	MANE Select	c.786T>C	p.Tyr262Tyr	synonymous	Exon 4 of 4	NP_006000.2
	TUBA1A	NM_001270399.2		c.786T>C	p.Tyr262Tyr	synonymous	Exon 4 of 4	NP_001257328.1
	TUBA1A	NM_001270400.2		c.681T>C	p.Tyr227Tyr	synonymous	Exon 4 of 4	NP_001257329.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA1A	ENST00000301071.12	TSL:1 MANE Select	c.786T>C	p.Tyr262Tyr	synonymous	Exon 4 of 4	ENSP00000301071.7
	TUBA1A	ENST00000550767.6	TSL:1	c.681T>C	p.Tyr227Tyr	synonymous	Exon 5 of 5	ENSP00000446637.1
	TUBA1A	ENST00000295766.9	TSL:2	c.786T>C	p.Tyr262Tyr	synonymous	Exon 4 of 4	ENSP00000439020.2

Frequencies

GnomAD3 genomes AF: 0.000901 AC: 137 AN: 152096 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000578

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000441 AC: 111 AN: 251418 AF XY: 0.000471

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000708

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000652

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000350 AC: 511 AN: 1461246 Hom.: 1 Cov.: 30 AF XY: 0.000367 AC XY: 267 AN XY: 726936

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

African (AFR) AF: 0.00147 AC: 49 AN: 33440

American (AMR) AF: 0.000783 AC: 35 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26106

East Asian (EAS) AF: 0.000808 AC: 32 AN: 39614

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86242

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000305 AC: 339 AN: 1111584

Other (OTH) AF: 0.000514 AC: 31 AN: 60360

⚠️ 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: 0.000900 AC: 137 AN: 152214 Hom.: 0 Cov.: 31 AF XY: 0.000981 AC XY: 73 AN XY: 74450

African (AFR) AF: 0.00202 AC: 84 AN: 41524

American (AMR) AF: 0.00111 AC: 17 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000578 AC: 2 AN: 3458

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000393 Hom.: 0

Bravo AF: 0.000858

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.6
DANN	Benign	0.57
PhyloP100		-0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs762008241; hg19: chr12-49579363; COSMIC: COSV55497241; COSMIC: COSV55497241;