16-89923406-G-A

Position:

• chr16-89923406-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The ENST00000315491.12(TUBB3):​c.5G>A​(p.Arg2Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBB3 ENST00000315491.12 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 5.10

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 16-89923406-G-A is Pathogenic according to our data. Variant chr16-89923406-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2108986.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB3	NM_006086.4	c.5G>A	p.Arg2Lys	missense_variant	1/4	ENST00000315491.12	NP_006077.2
TUBB3	NM_001197181.2	c.-160+1161G>A		intron_variant			NP_001184110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB3	ENST00000315491.12	c.5G>A	p.Arg2Lys	missense_variant	1/4	1	NM_006086.4	ENSP00000320295	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1357752 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 674040

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; This variant is associated with the following publications: (PMID: 20829227) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 11, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). This variant has not been reported in the literature in individuals affected with TUBB3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 2 of the TUBB3 protein (p.Arg2Lys). -

Complex cortical dysplasia with other brain malformations 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Aug 09, 2023

Criteria applied: PS2,PS4_MOD,PM2_SUP,PP2,PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T;T;T;.;T
Eigen	Benign	0.013
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.6	.;M;.;.;.
MutationTaster	Benign	0.58	D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.74	.;N;N;N;N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	.;.;D;D;D
Sift4G	Uncertain	0.052	T;T;T;T;T
Polyphen		0.0070	.;B;.;.;.
Vest4		0.42
MutPred		0.52		Gain of ubiquitination at R2 (P = 0.0162);Gain of ubiquitination at R2 (P = 0.0162);Gain of ubiquitination at R2 (P = 0.0162);Gain of ubiquitination at R2 (P = 0.0162);Gain of ubiquitination at R2 (P = 0.0162);
MVP		0.84
MPC		1.5
ClinPred		0.79	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.76
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr16-89989814;