16-89933512-G-A

Position:

• chr16-89933512-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000315491.12(TUBB3):​c.211G>A​(p.Gly71Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G71A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TUBB3 ENST00000315491.12 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.91

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 Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-89933513-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1338328.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBB3. . Gene score misZ 4.5786 (greater than the threshold 3.09). Trascript score misZ 5.665 (greater than threshold 3.09). GenCC has associacion of gene with tubulinopathy-associated dysgyria, complex cortical dysplasia with other brain malformations 1, congenital fibrosis of extraocular muscles, fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• PP5: Variant 16-89933512-G-A is Pathogenic according to our data. Variant chr16-89933512-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 219255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB3	NM_006086.4	c.211G>A	p.Gly71Arg	missense_variant	3/4	ENST00000315491.12	NP_006077.2
TUBB3	NM_001197181.2	c.-6G>A		5_prime_UTR_variant	3/4		NP_001184110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB3	ENST00000315491.12	c.211G>A	p.Gly71Arg	missense_variant	3/4	1	NM_006086.4	ENSP00000320295	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 11, 2023

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26639658, 27535533, 34562182, 33921132, 36494820) -

TUBB3-related tubulinopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

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

Mar 12, 2024

The p.Gly71Arg variant in TUBB3 was identified by our study in one individual with congenital fibrosis of the extraocular muscles, facial weakness, and simplified gyral pattern of the sylvian fissures, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). Trio genome analysis showed this variant to be de novo. The p.Gly71Arg variant in TUBB3 has been previously reported in 3 unrelated individuals with congenital fibrosis of the extraocular muscles and malformations of cortical brain development (PMID: 26639658). The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in these 3 individuals with confirmed paternity and maternity (PMID: 26639658). This variant has also been reported in ClinVar (Variation ID: 219255) and has been interpreted as pathogenic by GeneDx. This variant was absent from large population studies. The number of missense variants reported in TUBB3 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Gly71Ala, has been reported in association with disease in ClinVar, slightly supporting that a change at this position may not be tolerated (Variation ID: 1338328). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant congenital fibrosis of the extraocular muscles with or without extraocular involvement. ACMG/AMP Criteria applied: PS2_VeryStrong, PS4_Supporting, PM2_Supporting, PM5_supporting, PP2 (Richards 2015). -

TUBB3-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Feb 02, 2024

PS2, PS4, PM2, PP2 -

Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;T;D;T;.;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;T;T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.3	.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.9	D;.;D;D;D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;.;.;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D
Polyphen		1.0	.;.;D;.;.;.
Vest4		0.86
MutPred		0.61		.;Loss of catalytic residue at D74 (P = 0.0932);Loss of catalytic residue at D74 (P = 0.0932);Loss of catalytic residue at D74 (P = 0.0932);Loss of catalytic residue at D74 (P = 0.0932);Loss of catalytic residue at D74 (P = 0.0932);
MVP		0.96
MPC		3.0
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.97

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: rs864321715; hg19: chr16-89999920; COSMIC: COSV59247929; COSMIC: COSV59247929;