rs368743618

Positions:

chr2-219250552-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP2PP3_StrongPP5_Moderate

The NM_006000.3(TUBA4A):c.1147G>A(p.Ala383Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TUBA4A
NM_006000.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.88

Variant links:

Genes affected

TUBA4A (HGNC:12407): (tubulin alpha 4a) Microtubules of the eukaryotic cytoskeleton perform essential and diverse functions and are composed of a heterodimer of alpha and beta tubulin. The genes encoding these microtubule constituents are part of the tubulin superfamily, which is composed of six distinct families. Genes from the alpha, beta and gamma tubulin families are found in all eukaryotes. The alpha and beta tubulins represent the major components of microtubules, while gamma tubulin plays a critical role in the nucleation of microtubule assembly. There are multiple alpha and beta tubulin genes and they are highly conserved among and between species. This gene encodes an alpha tubulin that is a highly conserved homolog of a rat testis-specific alpha tubulin. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2013]

TUBA4A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBA4A. . Gene score misZ 3.3027 (greater than the threshold 3.09). Trascript score misZ 4.9936 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant macrothrombocytopenia, amyotrophic lateral sclerosis type 22.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 2-219250552-C-T is Pathogenic according to our data. Variant chr2-219250552-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180186.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-219250552-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBA4A	NM_006000.3 linkuse as main transcript	c.1147G>A	p.Ala383Thr	missense_variant	4/4	ENST00000248437.9	NP_005991.1	P68366-1
TUBA4A	NM_001278552.2 linkuse as main transcript	c.1102G>A	p.Ala368Thr	missense_variant	4/4		NP_001265481.1	P68366-2
TUBA4A	XM_047445674.1 linkuse as main transcript	c.1174G>A	p.Ala392Thr	missense_variant	4/4		XP_047301630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBA4A	ENST00000248437.9 linkuse as main transcript	c.1147G>A	p.Ala383Thr	missense_variant	4/4	1	NM_006000.3	ENSP00000248437.4		P68366-1
TUBA4A	ENST00000392088.6 linkuse as main transcript	c.1102G>A	p.Ala368Thr	missense_variant	4/4	2		ENSP00000375938.2		P68366-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251444

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 22

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Hannover Medical School	Sep 16, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 22, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

H;.

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.8

D;D

REVEL

Pathogenic

0.95

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.99

D;.

Vest4

0.92

MVP

0.96

MPC

1.9

ClinPred

0.87

GERP RS

5.0

Varity_R

0.91

gMVP

0.96

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over