rs587784487

Positions:

• chr12-49186409-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_006009.4(TUBA1A):​c.276T>C​(p.Leu92=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBA1A NM_006009.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.765

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031925946).
• BP6: Variant 12-49186409-A-G is Benign according to our data. Variant chr12-49186409-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 160153.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr12-49186409-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.765 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.276T>C	p.Leu92=	synonymous_variant	3/4	ENST00000301071.12
TUBA1A	NM_001270399.2	c.276T>C	p.Leu92=	synonymous_variant	3/4
TUBA1A	NM_001270400.2	c.171T>C	p.Leu57=	synonymous_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.276T>C	p.Leu92=	synonymous_variant	3/4	1	NM_006009.4	P1
TUBA1B-AS1	ENST00000656133.1	n.474-1874A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00 AC: 80 AN: 148626 Hom.: 0 Cov.: 30 FAILED QC

Gnomad AFR AF: 0.000371

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000475

Gnomad ASJ AF: 0.000593

Gnomad EAS AF: 0.000796

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00220

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000373

Gnomad OTH AF: 0.00196

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000234 AC: 34 AN: 1450738 Hom.: 0 Cov.: 49 AF XY: 0.0000208 AC XY: 15 AN XY: 721802

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000137

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000787

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.000157

Gnomad4 NFE exome AF: 0.00000903

Gnomad4 OTH exome AF: 0.0000501

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000538 AC: 80 AN: 148722 Hom.: 0 Cov.: 30 AF XY: 0.000689 AC XY: 50 AN XY: 72576

Gnomad4 AFR AF: 0.000370

Gnomad4 AMR AF: 0.000474

Gnomad4 ASJ AF: 0.000593

Gnomad4 EAS AF: 0.000797

Gnomad4 SAS AF: 0.000211

Gnomad4 FIN AF: 0.00220

Gnomad4 NFE AF: 0.000373

Gnomad4 OTH AF: 0.00195

Alfa AF: 0.00104 Hom.: 0

ExAC AF: 0.000939 AC: 114

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 22, 2015

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	10
DANN	Benign	0.95
Eigen	Benign	-0.050
Eigen_PC	Benign	-0.0078
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.13	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;N
PROVEAN	Benign	0.63	N
REVEL	Benign	0.081
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.57	T
Vest4		0.27
MVP		0.43
ClinPred		0.13	T
GERP RS		3.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1065671; hg19: chr12-49580192;