chr15-43386314-G-A

Position:

chr15-43386314-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_014444.5(TUBGCP4):c.998G>A(p.Arg333His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,497,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., cov: 24)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

TUBGCP4
NM_014444.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.65

Variant links:

Genes affected

TUBGCP4 (HGNC:16691): (tubulin gamma complex component 4) This gene encodes a component of the gamma-tubulin ring complex, which is required for microtubule nucleation. In mammalian cells, the protein localizes to centrosomes in association with gamma-tubulin. Crystal structure analysis revealed a structure composed of five helical bundles arranged around conserved hydrophobic cores. An exposed surface area located in the C-terminal domain is essential and sufficient for direct binding to gamma-tubulin. Mutations in this gene that alter microtubule organization are associated with microcephaly and chorioretinopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2015]

TUBGCP4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33129925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBGCP4	NM_014444.5 linkuse as main transcript	c.998G>A	p.Arg333His	missense_variant	9/18	ENST00000564079.6	NP_055259.2	Q9UGJ1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TUBGCP4	ENST00000564079.6 linkuse as main transcript	c.998G>A	p.Arg333His	missense_variant	9/18	1	NM_014444.5	ENSP00000456648.2	Q9UGJ1-2
TUBGCP4	ENST00000260383.11 linkuse as main transcript	c.998G>A	p.Arg333His	missense_variant	9/18	1		ENSP00000260383.7	Q9UGJ1-1
TUBGCP4	ENST00000561691.5 linkuse as main transcript	n.752G>A		non_coding_transcript_exon_variant	7/17	1		ENSP00000455474.1	H3BPU4

Frequencies

GnomAD3 genomes

AF:

0.0000803

AC:

AN:

124544

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000316

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000917

Gnomad EAS

AF:

0.00117

Gnomad SAS

AF:

0.000270

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000229

AC:

AN:

240396

Hom.:

AF XY:

0.000199

AC XY:

AN XY:

130934

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000252

Gnomad ASJ exome

AF:

0.00204

Gnomad EAS exome

AF:

0.000925

Gnomad SAS exome

AF:

0.000103

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000634

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.000125

AC:

172

AN:

1372464

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

683486

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000295

Gnomad4 ASJ exome

AF:

0.00170

Gnomad4 EAS exome

AF:

0.00156

Gnomad4 SAS exome

AF:

0.000170

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000408

Gnomad4 OTH exome

AF:

0.000145

GnomAD4 genome

AF:

0.0000802

AC:

AN:

124630

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

58538

show subpopulations

Gnomad4 AFR

AF:

0.0000315

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000917

Gnomad4 EAS

AF:

0.00117

Gnomad4 SAS

AF:

0.000270

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000163

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.000182

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 10, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 27, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 333 of the TUBGCP4 protein (p.Arg333His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TUBGCP4-related conditions. ClinVar contains an entry for this variant (Variation ID: 377341). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TUBGCP4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 07, 2017

- -

Microcephaly and chorioretinopathy 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.15

T;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;D

M_CAP

Benign

0.035

MetaRNN

Benign

0.33

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.9

D;D

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

1.0

D;D

Vest4

0.90

MVP

0.63

MPC

1.5

ClinPred

0.24

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.78

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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