rs587777355

Positions:

• chr6-30723957-A-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_178014.4(TUBB):​c.895A>G​(p.Met299Val) variant causes a missense change. 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBB NM_178014.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.12

Genes affected

TUBB (HGNC:20778): (tubulin beta class I) This gene encodes a beta tubulin protein. This protein forms a dimer with alpha tubulin and acts as a structural component of microtubules. Mutations in this gene cause cortical dysplasia, complex, with other brain malformations 6. Alternative splicing results in multiple splice variants. There are multiple pseudogenes for this gene on chromosomes 1, 6, 7, 8, 9, and 13. [provided by RefSeq, Jun 2014]

TUBB (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 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), TUBB. . Gene score misZ 5.6252 (greater than the threshold 3.09). Trascript score misZ 8.3435 (greater than threshold 3.09). GenCC has associacion of gene with multiple benign circumferential skin creases on limbs 1, complex cortical dysplasia with other brain malformations 6, multiple benign circumferential skin creases on limbs, TUBB3-related tubulinopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 6-30723957-A-G is Pathogenic according to our data. Variant chr6-30723957-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 127189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-30723957-A-G is described in UniProt as null. Variant chr6-30723957-A-G is described in UniProt as null. Variant chr6-30723957-A-G is described in UniProt as null. Variant chr6-30723957-A-G is described in UniProt as null. Variant chr6-30723957-A-G is described in UniProt as null. Variant chr6-30723957-A-G is described in UniProt as null. Variant chr6-30723957-A-G is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB	NM_178014.4	c.895A>G	p.Met299Val	missense_variant	4/4	ENST00000327892.13	NP_821133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB	ENST00000327892.13	c.895A>G	p.Met299Val	missense_variant	4/4	1	NM_178014.4	ENSP00000339001.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 6 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 04, 2024	Criteria applied: PS2,PS4_MOD,PS3_SUP,PM2_SUP,PP2,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 22, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 27, 2012	- -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.895A>G (p.M299V) alteration is located in exon 4 (coding exon 4) of the TUBB gene. This alteration results from an A to G substitution at nucleotide position 895, causing the methionine (M) at amino acid position 299 to be replaced by a valine (V). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been previously reported as a de novo occurrence in an individual with microcephaly, brain anomalies, developmental delay, ataxia, retinal dysplasia, and micro-ophthalmia (Breuss, 2012; Ngo, 2014). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 07, 2023

Published functional studies demonstrate impaired neuronal morphology, migration, microtubule assembly, and positioning (Breuss et al., 2012; Ngo et al., 2014); Not observed in large population cohorts (gnomAD); 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: 28347630, 23246003, 24833723, 32085672, 30738969, 28412269) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;.;D;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	3.4	M;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Pathogenic	0.87
Sift4G	Uncertain	0.035	D;D;D;D
Polyphen		0.39	B;.;.;.
Vest4		0.88
MutPred		0.87		Loss of sheet (P = 0.0817);.;.;.;
MVP		1.0
MPC		1.9
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.70
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: rs587777355; hg19: chr6-30691734;