rs1555394750

Variant names:

• chr15-43386230-A-C
• rs1555394750
• NM_014444.5:c.914A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014444.5(TUBGCP4):​c.914A>C​(p.Asp305Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: TUBGCP4 NM_014444.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.00
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• microcephaly and chorioretinopathy 3

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• microcephaly and chorioretinopathy 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014444.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBGCP4	NM_014444.5	MANE Select	c.914A>C	p.Asp305Ala	missense	Exon 9 of 18	NP_055259.2
	TUBGCP4	NM_001286414.3		c.914A>C	p.Asp305Ala	missense	Exon 9 of 18	NP_001273343.1	Q9UGJ1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBGCP4	ENST00000564079.6	TSL:1 MANE Select	c.914A>C	p.Asp305Ala	missense	Exon 9 of 18	ENSP00000456648.2	Q9UGJ1-2
	TUBGCP4	ENST00000260383.11	TSL:1	c.914A>C	p.Asp305Ala	missense	Exon 9 of 18	ENSP00000260383.7	Q9UGJ1-1
	TUBGCP4	ENST00000561691.5	TSL:1	n.668A>C		non_coding_transcript_exon	Exon 7 of 17	ENSP00000455474.1	H3BPU4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Benign	0.031
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		9.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.20
Sift	Benign	0.17	T
Sift4G	Benign	0.93	T
Polyphen		0.028	B
Vest4		0.85
MutPred		0.52		Loss of helix (P = 0.079)
MVP		0.41
MPC		1.1
ClinPred		0.75	D
GERP RS		5.7
Varity_R		0.42
gMVP		0.52

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

Other links and lift over

dbSNP: rs1555394750; hg19: chr15-43678428;