12-49185856-A-G

Variant names:

• chr12-49185856-A-G
• rs112023543
• NM_006009.4:c.510T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006009.4(TUBA1A):​c.510T>C​(p.Ser170Ser) variant causes a synonymous change. The variant allele was found at a frequency of 0.00702 in 1,609,874 control chromosomes in the GnomAD database, including 345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (149 hom., cov: 31)
  • Exomes 𝑓: 0.0049 (196 hom.)
• Consequence: TUBA1A NM_006009.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.87
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019606948).
• BP6: Variant 12-49185856-A-G is Benign according to our data. Variant chr12-49185856-A-G is described in ClinVar as Benign. ClinVar VariationId is 137849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0843 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA1A	NM_006009.4	MANE Select	c.510T>C	p.Ser170Ser	synonymous	Exon 4 of 4	NP_006000.2
	TUBA1A	NM_001270399.2		c.510T>C	p.Ser170Ser	synonymous	Exon 4 of 4	NP_001257328.1
	TUBA1A	NM_001270400.2		c.405T>C	p.Ser135Ser	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.510T>C	p.Ser170Ser	synonymous	Exon 4 of 4	ENSP00000301071.7
	TUBA1A	ENST00000550767.6	TSL:1	c.405T>C	p.Ser135Ser	synonymous	Exon 5 of 5	ENSP00000446637.1
	TUBA1A	ENST00000546918.1	TSL:3	c.662T>C	p.Leu221Pro	missense	Exon 3 of 3	ENSP00000446613.1

Frequencies

GnomAD3 genomes AF: 0.0272 AC: 4137 AN: 151874 Hom.: 144 Cov.: 31

Gnomad AFR AF: 0.0860

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.00434

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00602

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00418

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.00804 AC: 2018 AN: 250856 AF XY: 0.00707

Gnomad AFR exome AF: 0.0768

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.00378

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00358

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00489 AC: 7127 AN: 1457884 Hom.: 196 Cov.: 30 AF XY: 0.00476 AC XY: 3456 AN XY: 725448

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

African (AFR) AF: 0.0807 AC: 2609 AN: 32346

American (AMR) AF: 0.00546 AC: 244 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00437 AC: 114 AN: 26104

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39622

South Asian (SAS) AF: 0.00602 AC: 519 AN: 86178

European-Finnish (FIN) AF: 0.000861 AC: 46 AN: 53420

Middle Eastern (MID) AF: 0.00855 AC: 49 AN: 5728

European-Non Finnish (NFE) AF: 0.00280 AC: 3105 AN: 1109546

Other (OTH) AF: 0.00724 AC: 436 AN: 60228

⚠️ 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: 0.0274 AC: 4171 AN: 151990 Hom.: 149 Cov.: 31 AF XY: 0.0273 AC XY: 2025 AN XY: 74304

African (AFR) AF: 0.0866 AC: 3585 AN: 41384

American (AMR) AF: 0.0124 AC: 189 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00434 AC: 15 AN: 3458

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

South Asian (SAS) AF: 0.00623 AC: 30 AN: 4814

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10608

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00418 AC: 284 AN: 67980

Other (OTH) AF: 0.0228 AC: 48 AN: 2108

Alfa AF: 0.00388 Hom.: 3

ESP6500AA AF: 0.0645 AC: 284

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.0109 AC: 1327

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 31, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TUBA1A-related disorder Benign:1

Jul 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	9.5
DANN	Benign	0.92
Eigen	Benign	0.014
Eigen_PC	Benign	0.064
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.82	T
PhyloP100		3.9
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0070	D
Vest4		0.078
ClinPred		0.044	T
GERP RS		4.4
Mutation Taster		=44/56	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: rs112023543; hg19: chr12-49579639;