rs587777357

Variant names:

• chr6-30724263-G-A
• rs587777357
• NM_178014.4:c.1201G>A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_178014.4(TUBB):​c.1201G>A​(p.Glu401Lys) 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. 12/21 in silico tools predict a damaging 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:6
• Conservation: PhyloP100: 9.64

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the TUBB gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 26 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 5.6252 (above the threshold of 3.09). Trascript score misZ: 8.3435 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.894
• PP5: Variant 6-30724263-G-A is Pathogenic according to our data. Variant chr6-30724263-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 127191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-30724263-G-A is described in UniProt as null. Variant chr6-30724263-G-A is described in UniProt as null. Variant chr6-30724263-G-A is described in UniProt as null. Variant chr6-30724263-G-A is described in UniProt as null. Variant chr6-30724263-G-A is described in UniProt as null. Variant chr6-30724263-G-A is described in UniProt as null. Variant chr6-30724263-G-A is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB	NM_178014.4	c.1201G>A	p.Glu401Lys	missense_variant	Exon 4 of 4	ENST00000327892.13	NP_821133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB	ENST00000327892.13	c.1201G>A	p.Glu401Lys	missense_variant	Exon 4 of 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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple benign circumferential skin creases on limbs 1 Pathogenic:2

Aug 16, 2022

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.77; 3Cnet: 0.93). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000127191). The variant has been previously reported as de novo in a similarly affected individual (PMID: 23246003). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Complex cortical dysplasia with other brain malformations 6 Pathogenic:2

Dec 27, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 15, 2023

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TUBB c.1201G>A variant is classified as a PATHOGENIC variant (PS2, PS3, PS4_moderate, PM2, PP3). The TUBB c.1201G>A variant is a single nucleotide change in exon 4/4 of the TUBB gene, which is predicted to change the amino acid glutamic acid at position 401 in the protein to lysine. The variant is in dbSNP (rs587777357) but is absent from population databases (PM2). Additionally, the variant has been previously detected in multiple unrelated individuals with clinical features of microcephaly and neurodevelopmental disease (PMID: 23246003, 30738969, 35183200) (PS4_moderate). Functional studies have demonstrated that this variant disrupted the morphology of cortical neurons, resulting in defects in synaptic signaling and the polymerization rates of the microtuble cytoskeleton (PMID: 23246003, 24833723) (PS3). The patient is de novo for this variant (PS2). The variant has been reported in ClinVar (Variation ID: 127191) or HGMD (Accession no.: CM1212023) as Pathogenic/ disease causing. Computational prediction support a deleterious effect on the gene or gene product (PP3). Clinical review is recommended. -

Inborn genetic diseases Pathogenic:1

Jan 20, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Apr 23, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (PMID: 23246003, 24833723); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23246003, 24833723, 35183220, 30738969) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	T;.;T;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	4.1	H;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Pathogenic	0.77
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		0.90	P;.;.;.
Vest4		0.86
MutPred		0.51		Gain of methylation at E401 (P = 0.0022);.;.;.;
MVP		0.99
MPC		3.5
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.85
gMVP		0.99

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: rs587777357; hg19: chr6-30692040;