rs143759693

Positions:

chr22-50221166-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The ENST00000248846.10(TUBGCP6):c.3193G>A(p.Glu1065Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000762 in 1,608,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00078 ( 0 hom. )

Consequence

TUBGCP6
ENST00000248846.10 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.26

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.018829018).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000624 (95/152282) while in subpopulation NFE AF= 0.00126 (86/68020). AF 95% confidence interval is 0.00105. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TUBGCP6	NM_020461.4 linkuse as main transcript	c.3193G>A	p.Glu1065Lys	missense_variant	16/25	ENST00000248846.10	NP_065194.3
TUBGCP6	XR_001755343.3 linkuse as main transcript	n.3757G>A		non_coding_transcript_exon_variant	16/20
TUBGCP6	XR_938347.3 linkuse as main transcript	n.3757G>A		non_coding_transcript_exon_variant	16/23
TUBGCP6	XR_007067982.1 linkuse as main transcript	n.3048+862G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBGCP6	ENST00000248846.10 linkuse as main transcript	c.3193G>A	p.Glu1065Lys	missense_variant	16/25	1	NM_020461.4	ENSP00000248846	P1	Q96RT7-1
TUBGCP6	ENST00000439308.6 linkuse as main transcript	c.3193G>A	p.Glu1065Lys	missense_variant	16/25	1		ENSP00000397387
TUBGCP6	ENST00000498611.5 linkuse as main transcript	n.3617+109G>A		intron_variant, non_coding_transcript_variant		1
TUBGCP6	ENST00000491449.5 linkuse as main transcript	n.1500G>A		non_coding_transcript_exon_variant	8/16	5

Frequencies

GnomAD3 genomes

AF:

0.000624

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00126

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000441

AC:

111

AN:

251472

Hom.:

AF XY:

0.000434

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000861

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000777

AC:

1131

AN:

1455992

Hom.:

Cov.:

AF XY:

0.000739

AC XY:

535

AN XY:

724366

show subpopulations

Gnomad4 AFR exome

AF:

0.000210

Gnomad4 AMR exome

AF:

0.000203

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000465

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000950

Gnomad4 OTH exome

AF:

0.000964

GnomAD4 genome

AF:

0.000624

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00126

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000535

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000412

AC:

EpiCase

AF:

0.000981

EpiControl

AF:

0.00101

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1065 of the TUBGCP6 protein (p.Glu1065Lys). This variant is present in population databases (rs143759693, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. 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: 437152). 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.045

MetaRNN

Benign

0.019

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;.

MutationTaster

Benign

0.98

D;D

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.10

Sift

Benign

0.17

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.54

P;.

Vest4

0.22

MVP

0.36

MPC

0.51

ClinPred

0.052

GERP RS

4.2

Varity_R

0.060

gMVP

0.56

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