2-131478155-T-G

Variant names:

• chr2-131478155-T-G
• rs2695519
• NM_080386.4:c.4-9T>G

Variant summary

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

The NM_080386.4(TUBA3D):​c.4-9T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,609,860 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (40 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (33 hom.)
• Consequence: TUBA3D NM_080386.4 intron
• Scores: Splicing: ADA: 0.006317
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.340
• Publications: 1 publications found

Genes affected

TUBA3D (HGNC:24071): (tubulin alpha 3d) This gene encodes a member of the alpha tubulin family. Tubulin is a major component of microtubules, which are composed of alpha- and beta-tubulin heterodimers and microtubule-associated proteins in the cytoskeleton. Microtubules maintain cellular structure, function in intracellular transport, and play a role in spindle formation during mitosis. [provided by RefSeq, Oct 2011]

MZT2A (HGNC:33187): (mitotic spindle organizing protein 2A) Located in centrosome; cytosol; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-131478155-T-G is Benign according to our data. Variant chr2-131478155-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 788512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0129 (1965/152362) while in subpopulation AFR AF = 0.0434 (1804/41570). AF 95% confidence interval is 0.0417. There are 40 homozygotes in GnomAd4. There are 931 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080386.4. 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
	TUBA3D	NM_080386.4	MANE Select	c.4-9T>G		intron	N/A	NP_525125.2	P0DPH8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA3D	ENST00000321253.7	TSL:1 MANE Select	c.4-9T>G		intron	N/A	ENSP00000326042.6	P0DPH8
	MZT2A	ENST00000427024.5	TSL:3	n.278-5973A>C		intron	N/A	ENSP00000403353.1	H7C202
	MZT2A	ENST00000445782.2	TSL:2	n.331-5973A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1955 AN: 152248 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00765

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00176 AC: 440 AN: 249846 AF XY: 0.00135

Gnomad AFR exome AF: 0.0237

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.000800

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00104 AC: 1515 AN: 1457498 Hom.: 33 Cov.: 32 AF XY: 0.000917 AC XY: 664 AN XY: 724400

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

African (AFR) AF: 0.0328 AC: 1075 AN: 32734

American (AMR) AF: 0.00251 AC: 112 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.000807 AC: 21 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86126

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53380

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5754

European-Non Finnish (NFE) AF: 0.000127 AC: 141 AN: 1109102

Other (OTH) AF: 0.00249 AC: 150 AN: 60178

⚠️ 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 AF: 0.0129 AC: 1965 AN: 152362 Hom.: 40 Cov.: 33 AF XY: 0.0125 AC XY: 931 AN XY: 74508

African (AFR) AF: 0.0434 AC: 1804 AN: 41570

American (AMR) AF: 0.00764 AC: 117 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68040

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00680 Hom.: 0

Bravo AF: 0.0153

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	17
DANN	Benign	0.57
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0063
dbscSNV1_RF	Benign	0.17
SpliceAI score (max)		0.020		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: rs2695519; hg19: chr2-132235728;