2-219253758-A-G

Position:

• chr2-219253758-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006000.3(TUBA4A):​c.3+98T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,427,170 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (11 hom., cov: 32)
  • Exomes 𝑓: 0.014 (136 hom.)
• Consequence: TUBA4A NM_006000.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0240

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=-0.78).
• BP6: Variant 2-219253758-A-G is Benign according to our data. Variant chr2-219253758-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1218136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0098 (1492/152186) while in subpopulation NFE AF= 0.0145 (983/67984). AF 95% confidence interval is 0.0137. There are 11 homozygotes in gnomad4. There are 675 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1492 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBA4B	NM_001355221.1	c.12+339A>G		intron_variant		ENST00000490341.3	NP_001342150.1
TUBA4A	NM_006000.3	c.3+98T>C		intron_variant		ENST00000248437.9	NP_005991.1
TUBA4A	NM_001278552.2	c.-43+337T>C		intron_variant			NP_001265481.1
TUBA4A	XM_047445674.1	c.30+462T>C		intron_variant			XP_047301630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBA4A	ENST00000248437.9	c.3+98T>C		intron_variant		1	NM_006000.3	ENSP00000248437	P1
TUBA4B	ENST00000490341.3	c.12+339A>G		intron_variant		2	NM_001355221.1	ENSP00000487719	P1

Frequencies

GnomAD3 genomes AF: 0.00982 AC: 1493 AN: 152070 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00678

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.0135 AC: 17258 AN: 1274984 Hom.: 136 AF XY: 0.0133 AC XY: 8449 AN XY: 633008

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.0105

Gnomad4 ASJ exome AF: 0.0257

Gnomad4 EAS exome AF: 0.0000290

Gnomad4 SAS exome AF: 0.00535

Gnomad4 FIN exome AF: 0.00544

Gnomad4 NFE exome AF: 0.0151

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.00980 AC: 1492 AN: 152186 Hom.: 11 Cov.: 32 AF XY: 0.00907 AC XY: 675 AN XY: 74434

Gnomad4 AFR AF: 0.00280

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.0256

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.00678

Gnomad4 NFE AF: 0.0145

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0114 Hom.: 0

Bravo AF: 0.00994

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.2
DANN	Benign	0.58

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: rs45468095; hg19: chr2-220118480;