rs1056875

Variant names:

• chr12-49186397-T-C
• rs1056875
• NM_006009.4:c.288A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-49186397-T-C
• chr12-49186397-T-A
• chr12-49186397-T-G

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.288A>G​(p.Lys96Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 1,611,508 control chromosomes in the GnomAD database, including 128,464 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (17587 hom., cov: 30)
  • Exomes 𝑓: 0.38 (110877 hom.)
• Consequence: TUBA1A NM_006009.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.912
• 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=2.4875958E-6).
• BP6: Variant 12-49186397-T-C is Benign according to our data. Variant chr12-49186397-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 160154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.912 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.702 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.288A>G	p.Lys96Lys	synonymous	Exon 3 of 4	NP_006000.2
	TUBA1A	NM_001270399.2		c.288A>G	p.Lys96Lys	synonymous	Exon 3 of 4	NP_001257328.1	Q71U36-1
	TUBA1A	NM_001270400.2		c.183A>G	p.Lys61Lys	synonymous	Exon 3 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.288A>G	p.Lys96Lys	synonymous	Exon 3 of 4	ENSP00000301071.7	Q71U36-1
	TUBA1A	ENST00000550767.6	TSL:1	c.183A>G	p.Lys61Lys	synonymous	Exon 4 of 5	ENSP00000446637.1	Q71U36-2
	TUBA1A	ENST00000546918.1	TSL:3	c.440A>G	p.Lys147Arg	missense	Exon 2 of 3	ENSP00000446613.1	F8W0F6

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69357 AN: 151180 Hom.: 17540 Cov.: 30

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.721

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.420

GnomAD2 exomes AF: 0.421 AC: 105865 AN: 251354 AF XY: 0.421

Gnomad AFR exome AF: 0.667

Gnomad AMR exome AF: 0.360

Gnomad ASJ exome AF: 0.272

Gnomad EAS exome AF: 0.742

Gnomad FIN exome AF: 0.410

Gnomad NFE exome AF: 0.342

Gnomad OTH exome AF: 0.385

GnomAD4 exome AF: 0.379 AC: 553260 AN: 1460210 Hom.: 110877 Cov.: 90 AF XY: 0.381 AC XY: 277062 AN XY: 726440

African (AFR) AF: 0.672 AC: 22508 AN: 33470

American (AMR) AF: 0.361 AC: 16132 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 7235 AN: 26130

East Asian (EAS) AF: 0.718 AC: 28518 AN: 39696

South Asian (SAS) AF: 0.522 AC: 44962 AN: 86170

European-Finnish (FIN) AF: 0.410 AC: 21802 AN: 53192

Middle Eastern (MID) AF: 0.271 AC: 1519 AN: 5598

European-Non Finnish (NFE) AF: 0.348 AC: 386695 AN: 1111006

Other (OTH) AF: 0.396 AC: 23889 AN: 60310

GnomAD4 genome AF: 0.459 AC: 69466 AN: 151298 Hom.: 17587 Cov.: 30 AF XY: 0.463 AC XY: 34236 AN XY: 73894

African (AFR) AF: 0.664 AC: 27477 AN: 41350

American (AMR) AF: 0.381 AC: 5782 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 933 AN: 3466

East Asian (EAS) AF: 0.722 AC: 3710 AN: 5142

South Asian (SAS) AF: 0.551 AC: 2648 AN: 4804

European-Finnish (FIN) AF: 0.415 AC: 4328 AN: 10428

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

European-Non Finnish (NFE) AF: 0.346 AC: 23426 AN: 67658

Other (OTH) AF: 0.421 AC: 883 AN: 2098

Alfa AF: 0.497 Hom.: 12602

Bravo AF: 0.460

TwinsUK AF: 0.335 AC: 1243

ALSPAC AF: 0.358 AC: 1379

ESP6500AA AF: 0.661 AC: 2911

ESP6500EA AF: 0.330 AC: 2838

ExAC AF: 0.426 AC: 51686

EpiCase AF: 0.337

EpiControl AF: 0.330

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	1	Lissencephaly due to TUBA1A mutation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	9.9
DANN	Benign	0.93
Eigen	Benign	-0.067
Eigen_PC	Benign	-0.027
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0000025	T
MetaSVM	Benign	-0.92	T
PhyloP100		0.91
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.065
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.23	T
Vest4		0.047
ClinPred		0.039	T
GERP RS		3.4
Mutation Taster		=86/14	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: rs1056875; hg19: chr12-49580180; COSMIC: COSV55496614; COSMIC: COSV55496614;