2-219253809-G-C

Position:

• chr2-219253809-G-C

Variant summary

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

The NM_006000.3(TUBA4A):​c.3+47C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,533,286 control chromosomes in the GnomAD database, including 588,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (48316 hom., cov: 32)
  • Exomes 𝑓: 0.88 (540669 hom.)
• Consequence: TUBA4A NM_006000.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.184

Genes affected

TUBA4B (HGNC:18637): (tubulin alpha 4b) Predicted to enable GTP binding activity. Predicted to be a structural constituent of cytoskeleton. Predicted to be involved in microtubule cytoskeleton organization and mitotic cell cycle. Predicted to be active in cytoplasm and microtubule. [provided by Alliance of Genome Resources, Apr 2022]

TUBA4A (HGNC:12407): (tubulin alpha 4a) Microtubules of the eukaryotic cytoskeleton perform essential and diverse functions and are composed of a heterodimer of alpha and beta tubulin. The genes encoding these microtubule constituents are part of 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 and they are highly conserved among and between species. This gene encodes an alpha tubulin that is a highly conserved homolog of a rat testis-specific alpha tubulin. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-219253809-G-C is Benign according to our data. Variant chr2-219253809-G-C is described in ClinVar as [Benign]. Clinvar id is 1237057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBA4B	NM_001355221.1	c.12+390G>C		intron_variant		ENST00000490341.3	NP_001342150.1
TUBA4A	NM_006000.3	c.3+47C>G		intron_variant		ENST00000248437.9	NP_005991.1
TUBA4A	NM_001278552.2	c.-43+286C>G		intron_variant			NP_001265481.1
TUBA4A	XM_047445674.1	c.30+411C>G		intron_variant			XP_047301630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBA4A	ENST00000248437.9	c.3+47C>G		intron_variant		1	NM_006000.3	ENSP00000248437	P1
TUBA4B	ENST00000490341.3	c.12+390G>C		intron_variant		2	NM_001355221.1	ENSP00000487719	P1

Frequencies

GnomAD3 genomes AF: 0.774 AC: 117666 AN: 152062 Hom.: 48300 Cov.: 32

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.898

Gnomad AMR AF: 0.841

Gnomad ASJ AF: 0.849

Gnomad EAS AF: 0.844

Gnomad SAS AF: 0.802

Gnomad FIN AF: 0.953

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.902

Gnomad OTH AF: 0.777

GnomAD3 exomes AF: 0.840 AC: 118938 AN: 141608 Hom.: 51011 AF XY: 0.843 AC XY: 64132 AN XY: 76040

Gnomad AFR exome AF: 0.443

Gnomad AMR exome AF: 0.866

Gnomad ASJ exome AF: 0.819

Gnomad EAS exome AF: 0.835

Gnomad SAS exome AF: 0.795

Gnomad FIN exome AF: 0.950

Gnomad NFE exome AF: 0.889

Gnomad OTH exome AF: 0.846

GnomAD4 exome AF: 0.881 AC: 1217292 AN: 1381106 Hom.: 540669 Cov.: 34 AF XY: 0.880 AC XY: 600434 AN XY: 682134

Gnomad4 AFR exome AF: 0.449

Gnomad4 AMR exome AF: 0.860

Gnomad4 ASJ exome AF: 0.837

Gnomad4 EAS exome AF: 0.845

Gnomad4 SAS exome AF: 0.805

Gnomad4 FIN exome AF: 0.950

Gnomad4 NFE exome AF: 0.901

Gnomad4 OTH exome AF: 0.845

GnomAD4 genome AF: 0.773 AC: 117706 AN: 152180 Hom.: 48316 Cov.: 32 AF XY: 0.778 AC XY: 57885 AN XY: 74406

Gnomad4 AFR AF: 0.469

Gnomad4 AMR AF: 0.842

Gnomad4 ASJ AF: 0.849

Gnomad4 EAS AF: 0.844

Gnomad4 SAS AF: 0.802

Gnomad4 FIN AF: 0.953

Gnomad4 NFE AF: 0.902

Gnomad4 OTH AF: 0.778

Alfa AF: 0.830 Hom.: 9582

Bravo AF: 0.751

Asia WGS AF: 0.821 AC: 2856 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.65

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: rs939574; hg19: chr2-220118531;