rs587784487

Variant names:

• chr12-49186409-A-G
• rs1065671
• NM_006009.4:c.276T>C
• TUBA1A p.Leu92Leu

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_006009.4(TUBA1A):​c.276T>C​(p.Leu92Leu) 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
• 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: Likely_benign. The variant received -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 VariationId is 160153.
• BP7: Synonymous conserved (PhyloP=0.765 with no splicing effect.

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.276T>C	p.Leu92Leu	synonymous	Exon 3 of 4	NP_006000.2
	TUBA1A	NM_001270399.2		c.276T>C	p.Leu92Leu	synonymous	Exon 3 of 4	NP_001257328.1	Q71U36-1
	TUBA1A	NM_001270400.2		c.171T>C	p.Leu57Leu	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.276T>C	p.Leu92Leu	synonymous	Exon 3 of 4	ENSP00000301071.7	Q71U36-1
	TUBA1A	ENST00000550767.6	TSL:1	c.171T>C	p.Leu57Leu	synonymous	Exon 4 of 5	ENSP00000446637.1	Q71U36-2
	TUBA1A	ENST00000546918.1	TSL:3	c.428T>C	p.Leu143Ser	missense	Exon 2 of 3	ENSP00000446613.1	F8W0F6

Frequencies

GnomAD3 genomes AF: 0.000538 AC: 80 AN: 148626 Hom.: 0 Cov.: 30

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

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 249856 AF XY: 0.0000370

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.0000587

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

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

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

African (AFR) AF: 0.00 AC: 0 AN: 33348

American (AMR) AF: 0.000137 AC: 6 AN: 43696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25692

East Asian (EAS) AF: 0.0000787 AC: 3 AN: 38118

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85658

European-Finnish (FIN) AF: 0.000157 AC: 8 AN: 50994

Middle Eastern (MID) AF: 0.000358 AC: 2 AN: 5590

European-Non Finnish (NFE) AF: 0.00000903 AC: 10 AN: 1107818

Other (OTH) AF: 0.0000501 AC: 3 AN: 59824

⚠️ 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 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

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

African (AFR) AF: 0.000370 AC: 15 AN: 40578

American (AMR) AF: 0.000474 AC: 7 AN: 14754

Ashkenazi Jewish (ASJ) AF: 0.000593 AC: 2 AN: 3372

East Asian (EAS) AF: 0.000797 AC: 4 AN: 5016

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4730

European-Finnish (FIN) AF: 0.00220 AC: 22 AN: 9994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000373 AC: 25 AN: 67080

Other (OTH) AF: 0.00195 AC: 4 AN: 2052

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00104 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
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
PhyloP100		0.77
PROVEAN	Benign	0.63	N
REVEL	Benign	0.081
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.57	T
Mutation Taster		=52/48	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1065671;

hg19: chr12-49580192;