rs199717430

Variant names:

• chr12-49186601-G-A
• rs199717430
• NM_006009.4:c.226+10C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006009.4(TUBA1A):​c.226+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 1,613,994 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00084 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (14 hom.)
• Consequence: TUBA1A NM_006009.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.747
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005897194).
• BP6: Variant 12-49186601-G-A is Benign according to our data. Variant chr12-49186601-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 160152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000709 (1037/1461718) while in subpopulation MID AF = 0.0347 (200/5768). AF 95% confidence interval is 0.0307. There are 14 homozygotes in GnomAdExome4. There are 534 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check.
• BS2: High AC in GnomAd4 at 128 AD gene.

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.226+10C>T		intron	N/A	NP_006000.2
	TUBA1A	NM_001270399.2		c.226+10C>T		intron	N/A	NP_001257328.1	Q71U36-1
	TUBA1A	NM_001270400.2		c.121+10C>T		intron	N/A	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.226+10C>T		intron	N/A	ENSP00000301071.7	Q71U36-1
	TUBA1A	ENST00000550767.6	TSL:1	c.121+10C>T		intron	N/A	ENSP00000446637.1	Q71U36-2
	TUBA1A	ENST00000546918.1	TSL:3	c.236C>T	p.Thr79Ile	missense	Exon 2 of 3	ENSP00000446613.1	F8W0F6

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000887 AC: 223 AN: 251358 AF XY: 0.000942

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00379

Gnomad NFE exome AF: 0.000800

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.000709 AC: 1037 AN: 1461718 Hom.: 14 Cov.: 38 AF XY: 0.000734 AC XY: 534 AN XY: 727158

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.000604 AC: 27 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000638 AC: 55 AN: 86236

European-Finnish (FIN) AF: 0.00367 AC: 196 AN: 53416

Middle Eastern (MID) AF: 0.0347 AC: 200 AN: 5768

European-Non Finnish (NFE) AF: 0.000430 AC: 478 AN: 1111910

Other (OTH) AF: 0.00113 AC: 68 AN: 60390

GnomAD4 genome AF: 0.000841 AC: 128 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.000994 AC XY: 74 AN XY: 74452

African (AFR) AF: 0.000144 AC: 6 AN: 41572

American (AMR) AF: 0.000785 AC: 12 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4822

European-Finnish (FIN) AF: 0.00405 AC: 43 AN: 10618

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68012

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00100 Hom.: 0

Bravo AF: 0.000555

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000708 AC: 86

EpiCase AF: 0.00104

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	not specified (1)
-	-	1	TUBA1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.90
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.71	T
PhyloP100		0.75
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.055
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.058	T
Vest4		0.12
MVP		0.56
ClinPred		0.031	T
GERP RS		3.0
Mutation Taster		=97/3	polymorphism

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: rs199717430; hg19: chr12-49580384;