rs587784507

chr16-89935191-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_006086.4(TUBB3):c.740A>G(p.Asn247Ser) 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. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N247N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TUBB3 NM_006086.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.16

Genes affected

TUBB3 (HGNC:20772): (tubulin beta 3 class III) This gene encodes a class III member of the beta tubulin protein family. Beta tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. This protein is primarily expressed in neurons and may be involved in neurogenesis and axon guidance and maintenance. Mutations in this gene are the cause of congenital fibrosis of the extraocular muscles type 3. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 6. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006086.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TUBB3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB3	NM_006086.4	c.740A>G	p.Asn247Ser	missense_variant	4/4	ENST00000315491.12
TUBB3	NM_001197181.2	c.524A>G	p.Asn175Ser	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB3	ENST00000315491.12	c.740A>G	p.Asn247Ser	missense_variant	4/4	1	NM_006086.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 29, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	21
Dann	Benign	0.91
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.4	D;D;D;D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		0.92	.;.;.;P
Vest4		0.77
MutPred		0.86		.;.;.;Gain of methylation at K252 (P = 0.1087);
MVP		0.94
MPC		1.8
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.97
gMVP		0.98

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: rs587784507; hg19: chr16-90001599;