15-23008846-A-C

Position:

• chr15-23008846-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_052903.6(TUBGCP5):​c.2180T>G​(p.Phe727Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBGCP5 NM_052903.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.46

Genes affected

TUBGCP5 (HGNC:18600): (tubulin gamma complex component 5) Enables microtubule binding activity. Involved in microtubule nucleation. Located in centrosome and cytosol. Part of gamma-tubulin large complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBGCP5	NM_052903.6	c.2180T>G	p.Phe727Cys	missense_variant	16/23	ENST00000615383.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBGCP5	ENST00000615383.5	c.2180T>G	p.Phe727Cys	missense_variant	16/23	1	NM_052903.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephaly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Apr 10, 2018

We report a novel homozygous missense mutation in the TUBGCP5 gene (tubulin gamma complex associated protein 5) in a patient with microcephaly and mild developmental delay. This is a rare homozygous missense variant in the TUBGCP5 gene (c.2180T>G) in the patient, causing an amino-acid substitution of phenylalanine to cysteine at position 727 of the protein (TUBGCP5:p.Phe727Cys). This position is extremely conserved, as shown by population allele frequency data from ExAC and GnomAD, as well as comparisons with all other vertebrates. Furthermore, several of the known genes associated with MCPH are involved in the formation and function of the centrosome, including two paralogs of TUBGCP5; TUBGCP4 and TUBGCP6, also supporting our hypothesis. The identified recessive homozygous missense mutation in TUBGCP5 may thus represent a novel cause of MCPH with mild developmental delay. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Pathogenic	0.89	D;D
Sift4G	Uncertain	0.0020	D;D
Vest4		0.94
gMVP		0.98

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: rs1555436162; hg19: chr15-22864222;