12-49128209-C-G

Variant names:

• chr12-49128209-C-G
• NM_006082.3:c.1105G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006082.3(TUBA1B):​c.1105G>C​(p.Ala369Pro) 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: 31)
• Consequence: TUBA1B NM_006082.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88

Genes affected

TUBA1B (HGNC:18809): (tubulin alpha 1b) Enables double-stranded RNA binding activity and ubiquitin protein ligase binding activity. Predicted to be involved in microtubule cytoskeleton organization and mitotic cell cycle. Predicted to act upstream of or within cellular response to interleukin-4. Located in microtubule. [provided by Alliance of Genome Resources, Apr 2022]

TUBA1B-AS1 (HGNC:56356): (TUBA1B antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA1B	NM_006082.3	c.1105G>C	p.Ala369Pro	missense_variant	Exon 4 of 4	ENST00000336023.9	NP_006073.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA1B	ENST00000336023.9	c.1105G>C	p.Ala369Pro	missense_variant	Exon 4 of 4	1	NM_006082.3	ENSP00000336799.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuromuscular disease Uncertain:1

Nov 22, 2024

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Ala369Pro variant in TUBA1B was identified by our study in 1 individual with neuromuscular disease. While this gene is still lacking sufficient evidence to establish a gene-disease relationship, we believe this is a possible novel gene candidate for neuromuscular disease. Given the limited information about this gene-disease relationship, the significance of the p.Ala369Pro variant is uncertain. If you have any additional information about functional evidence or other individuals with this phenotype that also have variants in TUBA1B we encourage you to reach out to us. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	H
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.80
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.75		Gain of sheet (P = 0.0477);
MVP		0.99
MPC		4.3
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		1.0

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: chr12-49521992;