rs730880025

Positions:

chr2-219250741-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 7P and 4B. PP2PP3_StrongPP5_ModerateBS2

The NM_006000.3(TUBA4A):c.958C>T(p.Arg320Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,118 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

TUBA4A
NM_006000.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.02

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:

TUBA4A (HGNC:):

TUBA4A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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, 0.974

PP5

Variant 2-219250741-G-A is Pathogenic according to our data. Variant chr2-219250741-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180182.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBA4A	NM_006000.3 linkuse as main transcript	c.958C>T	p.Arg320Cys	missense_variant	4/4	ENST00000248437.9	NP_005991.1	P68366-1
TUBA4A	NM_001278552.2 linkuse as main transcript	c.913C>T	p.Arg305Cys	missense_variant	4/4		NP_001265481.1	P68366-2
TUBA4A	XM_047445674.1 linkuse as main transcript	c.985C>T	p.Arg329Cys	missense_variant	4/4		XP_047301630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TUBA4A	ENST00000248437.9 linkuse as main transcript	c.958C>T	p.Arg320Cys	missense_variant	4/4	1	NM_006000.3	ENSP00000248437.4	P68366-1
TUBA4A	ENST00000392088.6 linkuse as main transcript	c.913C>T	p.Arg305Cys	missense_variant	4/4	2		ENSP00000375938.2	P68366-2
TUBA4A	ENST00000498660.1 linkuse as main transcript	n.778C>T		non_coding_transcript_exon_variant	3/3	3
TUBA4A	ENST00000398989.2 linkuse as main transcript	c.*31C>T		downstream_gene_variant		3		ENSP00000396212.1	C9JDS9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

251488

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

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

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 22

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 22, 2014

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 09, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect on protein binding (Smith et al., 214; Ganne et al., 2023); This variant is associated with the following publications: (PMID: 26465396, 31585128, 31574570, 28412269, 25374358, 33378215, 34830115, 34169147, 36747013) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

4.4

H;.

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.2

D;D

REVEL

Pathogenic

0.97

Sift4G

Uncertain

0.050

T;D

Polyphen

0.92

P;.

Vest4

0.83

MutPred

0.88

Gain of sheet (P = 0.0827);.;

MVP

0.95

MPC

2.5

ClinPred

0.96

GERP RS

5.3

Varity_R

0.69

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

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