22-50220827-T-C

Position:

• chr22-50220827-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020461.4(TUBGCP6):​c.3532A>G​(p.Met1178Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 27)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBGCP6 NM_020461.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0290

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017602265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBGCP6	NM_020461.4	c.3532A>G	p.Met1178Val	missense_variant	16/25	ENST00000248846.10	NP_065194.3
TUBGCP6	XR_001755343.3	n.4096A>G		non_coding_transcript_exon_variant	16/20
TUBGCP6	XR_938347.3	n.4096A>G		non_coding_transcript_exon_variant	16/23
TUBGCP6	XR_007067982.1	n.3049-812A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBGCP6	ENST00000248846.10	c.3532A>G	p.Met1178Val	missense_variant	16/25	1	NM_020461.4	ENSP00000248846	P1
TUBGCP6	ENST00000439308.6	c.3532A>G	p.Met1178Val	missense_variant	16/25	1		ENSP00000397387
TUBGCP6	ENST00000498611.5	n.3617+448A>G		intron_variant, non_coding_transcript_variant		1
TUBGCP6	ENST00000491449.5	n.1839A>G		non_coding_transcript_exon_variant	8/16	5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 125 AN: 84186 Hom.: 0 Cov.: 27 FAILED QC

Gnomad AFR AF: 0.00230

Gnomad AMI AF: 0.00251

Gnomad AMR AF: 0.00208

Gnomad ASJ AF: 0.000894

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00127

Gnomad FIN AF: 0.00205

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000969

Gnomad OTH AF: 0.00247

GnomAD3 exomes AF: 0.00000435 AC: 1 AN: 229718 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 125268

Gnomad AFR exome AF: 0.00

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: 0.00000937

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.76e-7 AC: 1 AN: 1289200 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 641196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000276

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00148 AC: 125 AN: 84250 Hom.: 0 Cov.: 27 AF XY: 0.00133 AC XY: 55 AN XY: 41296

Gnomad4 AFR AF: 0.00229

Gnomad4 AMR AF: 0.00207

Gnomad4 ASJ AF: 0.000894

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00127

Gnomad4 FIN AF: 0.00205

Gnomad4 NFE AF: 0.000969

Gnomad4 OTH AF: 0.00245

Alfa AF: 0.0599 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 24, 2022

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1178 of the TUBGCP6 protein (p.Met1178Val). 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 TUBGCP6-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.040
DANN	Benign	0.48
DEOGEN2	Benign	0.011	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.042	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.7	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.1	N;N
REVEL	Benign	0.023
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.080
MutPred		0.26		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.072
MPC		0.11
ClinPred		0.030	T
GERP RS		1.2
Varity_R		0.023
gMVP		0.14

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

Other links and lift over

dbSNP: rs1215314321; hg19: chr22-50659256;