chr12-49186412-T-C

Variant names:

• chr12-49186412-T-C
• rs765483435
• NM_006009.4:c.273A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_006009.4(TUBA1A):​c.273A>G​(p.Gln91Gln) 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 0.00057 (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:3
• Conservation: PhyloP100: 3.21
• Publications: 2 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 -1 ACMG points.

• BP6: Variant 12-49186412-T-C is Benign according to our data. Variant chr12-49186412-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212492.

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.273A>G	p.Gln91Gln	synonymous	Exon 3 of 4	NP_006000.2
	TUBA1A	NM_001270399.2		c.273A>G	p.Gln91Gln	synonymous	Exon 3 of 4	NP_001257328.1
	TUBA1A	NM_001270400.2		c.168A>G	p.Gln56Gln	synonymous	Exon 3 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.273A>G	p.Gln91Gln	synonymous	Exon 3 of 4	ENSP00000301071.7
	TUBA1A	ENST00000550767.6	TSL:1	c.168A>G	p.Gln56Gln	synonymous	Exon 4 of 5	ENSP00000446637.1
	TUBA1A	ENST00000546918.1	TSL:3	c.425A>G	p.Asn142Ser	missense	Exon 2 of 3	ENSP00000446613.1

Frequencies

GnomAD3 genomes AF: 0.000569 AC: 85 AN: 149280 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000678

Gnomad ASJ AF: 0.000593

Gnomad EAS AF: 0.000795

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00270

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000447

Gnomad OTH AF: 0.00196

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 249848 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000588

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000234 AC: 34 AN: 1450206 Hom.: 0 Cov.: 46 AF XY: 0.0000236 AC XY: 17 AN XY: 721540

⚠️ 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: 33358

American (AMR) AF: 0.000114 AC: 5 AN: 43678

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

East Asian (EAS) AF: 0.000105 AC: 4 AN: 38078

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85634

European-Finnish (FIN) AF: 0.000157 AC: 8 AN: 50944

Middle Eastern (MID) AF: 0.000358 AC: 2 AN: 5582

European-Non Finnish (NFE) AF: 0.00000903 AC: 10 AN: 1107402

Other (OTH) AF: 0.0000334 AC: 2 AN: 59838

⚠️ 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: 0.000569 AC: 85 AN: 149378 Hom.: 0 Cov.: 30 AF XY: 0.000741 AC XY: 54 AN XY: 72884

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

African (AFR) AF: 0.000170 AC: 7 AN: 41146

American (AMR) AF: 0.000678 AC: 10 AN: 14760

Ashkenazi Jewish (ASJ) AF: 0.000593 AC: 2 AN: 3370

East Asian (EAS) AF: 0.000797 AC: 4 AN: 5020

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4760

European-Finnish (FIN) AF: 0.00270 AC: 27 AN: 10006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000447 AC: 30 AN: 67118

Other (OTH) AF: 0.00194 AC: 4 AN: 2058

⚠️ 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: 0.00158 Hom.: 0

ExAC AF: 0.000898 AC: 109

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	not specified (1)
-	-	1	TUBA1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	15
DANN	Benign	0.73
Eigen	Benign	0.016
Eigen_PC	Benign	0.062
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.69	T
PhyloP100		3.2
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.80	T
Vest4		0.20
MVP		0.63
ClinPred		0.17	T
GERP RS		3.4
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs765483435; hg19: chr12-49580195; COSMIC: COSV105889674; COSMIC: COSV105889674;