18-12325164-G-C

Variant summary

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

The NM_032525.3(TUBB6):c.375G>C(p.Glu125Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,430 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TUBB6 NM_032525.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.966

Genes affected

TUBB6 (HGNC:20776): (tubulin beta 6 class V) Predicted to enable GTP binding activity. Predicted to be a structural constituent of cytoskeleton. Predicted to be involved in microtubule cytoskeleton organization and mitotic cell cycle. Located in microtubule. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB6	NM_032525.3	c.375G>C	p.Glu125Asp	missense_variant	4/4	ENST00000317702.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB6	ENST00000317702.10	c.375G>C	p.Glu125Asp	missense_variant	4/4	1	NM_032525.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461430 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726976

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Facial palsy, congenital, with ptosis and velopharyngeal dysfunction Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

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

Mar 12, 2024

The heterozygous p.Glu125Asp variant in TUBB6 was identified by our study in one individual with congenital fibrosis of the extraocular muscles, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). The variant was identified by trio genome analysis and was inherited from the reportedly unaffected father of this individual. The p.Glu125Asp variant in TUBB6 has not been previously reported in individuals with congenital facial palsy with ptosis and velopharyngeal dysfunction. This variant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Glu125Asp variant in TUBB6 is uncertain. ACMG/AMP Criteria applied: PM2_Supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Benign	-0.30	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
Sift4G	Uncertain	0.034	D;D;D;D
Polyphen		0.84	.;P;.;.
Vest4		0.76
MutPred		0.82		Gain of catalytic residue at E125 (P = 0.059);Gain of catalytic residue at E125 (P = 0.059);.;.;
MVP		0.79
MPC		1.8
ClinPred		0.92	D
GERP RS		4.0
Varity_R		0.50
gMVP		0.87

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: rs144890684; hg19: chr18-12325163;