chr22-50228015-C-T

Position:

chr22-50228015-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_020461.4(TUBGCP6):c.1304G>A(p.Gly435Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000641 in 1,560,162 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

TUBGCP6
NM_020461.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.92

Variant links:

Genes affected

TUBGCP6 (HGNC:18127): (tubulin gamma complex component 6) The protein encoded by this gene is part of a large multisubunit complex required for microtubule nucleation at the centrosome. [provided by RefSeq, Jul 2008]

TUBGCP6 links:

TUBGCP6 (HGNC:):

TUBGCP6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBGCP6	NM_020461.4 linkuse as main transcript	c.1304G>A	p.Gly435Asp	missense_variant	5/25	ENST00000248846.10	NP_065194.3	Q96RT7-1
TUBGCP6	XR_001755343.3 linkuse as main transcript	n.1868G>A		non_coding_transcript_exon_variant	5/20
TUBGCP6	XR_007067982.1 linkuse as main transcript	n.1868G>A		non_coding_transcript_exon_variant	5/19
TUBGCP6	XR_938347.3 linkuse as main transcript	n.1868G>A		non_coding_transcript_exon_variant	5/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TUBGCP6	ENST00000248846.10 linkuse as main transcript	c.1304G>A	p.Gly435Asp	missense_variant	5/25	1	NM_020461.4	ENSP00000248846.5	Q96RT7-1
TUBGCP6	ENST00000439308.6 linkuse as main transcript	c.1304G>A	p.Gly435Asp	missense_variant	5/25	1		ENSP00000397387.2	E7EQL8
TUBGCP6	ENST00000498611.5 linkuse as main transcript	n.1837G>A		non_coding_transcript_exon_variant	5/23	1
TUBGCP6	ENST00000434349.1 linkuse as main transcript	c.533G>A	p.Gly178Asp	missense_variant	4/6	5		ENSP00000409650.1	H7C358

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000580

AC:

AN:

172368

Hom.:

AF XY:

0.0000110

AC XY:

AN XY:

90986

show subpopulations

Gnomad AFR exome

AF:

0.0000897

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:

0.00000355

AC:

AN:

1407942

Hom.:

Cov.:

AF XY:

0.00000288

AC XY:

AN XY:

694726

show subpopulations

Gnomad4 AFR exome

AF:

0.0000914

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.22e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000121

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000332

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000171

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 11, 2014

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

The c.1304G>A (p.G435D) alteration is located in exon 5 (coding exon 5) of the TUBGCP6 gene. This alteration results from a G to A substitution at nucleotide position 1304, causing the glycine (G) at amino acid position 435 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2022

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 435 of the TUBGCP6 protein (p.Gly435Asp). This variant is present in population databases (rs368378157, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TUBGCP6-related conditions. ClinVar contains an entry for this variant (Variation ID: 212505). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

M;.

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-4.9

D;D

REVEL

Uncertain

0.38

Sift

Uncertain

0.013

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.87

MVP

0.56

MPC

0.60

ClinPred

0.94

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.85

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