TUBB3 p.Gly71Arg

Variant names:

• chr16-89933512-G-C
• NM_006086.4:c.211G>C
• TUBB3 p.Gly71Arg

Your query was ambiguous. Multiple possible variants found:

• chr16-89933512-G-C
• chr16-89933512-G-A
• chr16-89933512-GGA-CGT
• chr16-89933512-GGA-CGC
• chr16-89933512-GGA-CGG
• chr16-89933512-GGA-AGG

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS1_Very_Strong PM2 PM5 PP2 PP3_Moderate

The NM_006086.4(TUBB3):​c.211G>C​(p.Gly71Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. 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)
• Consequence: TUBB3 NM_006086.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.91
• Publications: 0 publications found

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]

TUBB3 Gene-Disease associations (from GenCC):

• TUBB3-related tubulinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• complex cortical dysplasia with other brain malformations 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Illumina, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement

  Inheritance: AD Classification: STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital fibrosis of extraocular muscles

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tubulinopathy-associated dysgyria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000198211 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS1: Transcript NM_006086.4 (TUBB3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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 VariationId is 1338328.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the TUBB3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 4.5786 (above the threshold of 3.09). Trascript score misZ: 5.665 (above the threshold of 3.09). GenCC associations: The gene is linked to fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement, complex cortical dysplasia with other brain malformations 1, tubulinopathy-associated dysgyria, congenital fibrosis of extraocular muscles, TUBB3-related tubulinopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006086.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB3	NM_006086.4	MANE Select	c.211G>C	p.Gly71Arg	missense	Exon 3 of 4	NP_006077.2	Q13509-1
	TUBB3	NM_001197181.2		c.-6G>C		5_prime_UTR	Exon 3 of 4	NP_001184110.1	Q13509-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB3	ENST00000315491.12	TSL:1 MANE Select	c.211G>C	p.Gly71Arg	missense	Exon 3 of 4	ENSP00000320295.7	Q13509-1
	ENSG00000198211	ENST00000556922.1	TSL:2	c.1252G>C	p.Gly418Arg	missense	Exon 4 of 5	ENSP00000451560.1	A0A0B4J269
	TUBB3	ENST00000557262.5	TSL:1	n.*194G>C		non_coding_transcript_exon	Exon 4 of 5	ENSP00000451985.1	G3V4U2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr16-89999920;