12-49185856-A-G

Position:

• chr12-49185856-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006009.4(TUBA1A):​c.510T>C​(p.Ser170=) 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

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

Verdict is Benign. Variant got -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 id is 137849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49185856-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBA1A	NM_006009.4	c.510T>C	p.Ser170=	synonymous_variant	4/4	ENST00000301071.12	NP_006000.2
TUBA1A	NM_001270399.2	c.510T>C	p.Ser170=	synonymous_variant	4/4		NP_001257328.1
TUBA1A	NM_001270400.2	c.405T>C	p.Ser135=	synonymous_variant	4/4		NP_001257329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBA1A	ENST00000301071.12	c.510T>C	p.Ser170=	synonymous_variant	4/4	1	NM_006009.4	ENSP00000301071	P1
TUBA1B-AS1	ENST00000656133.1	n.474-2427A>G		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.00804 AC: 2018 AN: 250856 Hom.: 72 AF XY: 0.00707 AC XY: 960 AN XY: 135706

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 SAS exome AF: 0.00582

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

Gnomad4 AFR exome AF: 0.0807

Gnomad4 AMR exome AF: 0.00546

Gnomad4 ASJ exome AF: 0.00437

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00602

Gnomad4 FIN exome AF: 0.000861

Gnomad4 NFE exome AF: 0.00280

Gnomad4 OTH exome AF: 0.00724

GnomAD4 genome AF: 0.0274 AC: 4171 AN: 151990 Hom.: 149 Cov.: 31 AF XY: 0.0273 AC XY: 2025 AN XY: 74304

Gnomad4 AFR AF: 0.0866

Gnomad4 AMR AF: 0.0124

Gnomad4 ASJ AF: 0.00434

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00623

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00418

Gnomad4 OTH AF: 0.0228

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

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2014	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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

TUBA1A-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2019

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 v4.3

Name	Calibrated prediction	Score	Prediction
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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs112023543; hg19: chr12-49579639;