chr2-130192039-G-C

Variant names:

• chr2-130192039-G-C
• rs748996131
• NM_207312.3:c.1145C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_207312.3(TUBA3E):​c.1145C>G​(p.Thr382Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: TUBA3E NM_207312.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.27

Genes affected

TUBA3E (HGNC:20765): (tubulin alpha 3e) 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. This gene encodes an alpha tubulin that highly conserved among species. A missense mutation in this gene has been potentially linked to microlissencephaly and global developmental delay. [provided by RefSeq, Jul 2016]

MZT2B (HGNC:25886): (mitotic spindle organizing protein 2B) Located in cytosol; microtubule cytoskeleton; and nucleoplasm. Part of gamma-tubulin large complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA3E	NM_207312.3	c.1145C>G	p.Thr382Arg	missense_variant	Exon 5 of 5	ENST00000312988.9	NP_997195.2
MZT2B	XM_047445914.1	c.319+9264G>C		intron_variant	Intron 2 of 3		XP_047301870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA3E	ENST00000312988.9	c.1145C>G	p.Thr382Arg	missense_variant	Exon 5 of 5	1	NM_207312.3	ENSP00000318197.7

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	5.1	H
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.87
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.87		Gain of MoRF binding (P = 0.0084);
MVP		0.93
ClinPred		0.96	D
GERP RS		3.0
Varity_R		0.84
gMVP		0.80

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: rs748996131; hg19: chr2-130949612;