2-130194171-T-G

Variant names:

• chr2-130194171-T-G
• NM_207312.3:c.671A>C

Variant summary

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

The NM_207312.3(TUBA3E):​c.671A>C​(p.Tyr224Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TUBA3E NM_207312.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.23

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, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA3E	NM_207312.3	c.671A>C	p.Tyr224Ser	missense_variant	Exon 4 of 5	ENST00000312988.9	NP_997195.2
MZT2B	XM_047445914.1	c.320-8154T>G		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.671A>C	p.Tyr224Ser	missense_variant	Exon 4 of 5	1	NM_207312.3	ENSP00000318197.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 151

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.671A>C (p.Y224S) alteration is located in exon 4 (coding exon 4) of the TUBA3E gene. This alteration results from a A to C substitution at nucleotide position 671, causing the tyrosine (Y) at amino acid position 224 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Benign	0.94
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.44
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.074	D
MutationAssessor	Pathogenic	4.7	H
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.57
Sift4G	Pathogenic	0.0010	D
Polyphen		0.91	P
Vest4		0.84
MutPred		0.83		Gain of disorder (P = 0.0134);
MVP		0.86
ClinPred		1.0	D
GERP RS		1.7
Varity_R		0.88
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-130951744;