15-43403768-G-T

Variant names:

• chr15-43403768-G-T
• rs769082991
• NM_014444.5:c.1817G>T

Variant summary

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

The NM_014444.5(TUBGCP4):​c.1817G>T​(p.Arg606Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R606C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TUBGCP4 NM_014444.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.92
• 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]

TP53BP1 (HGNC:11999): (tumor protein p53 binding protein 1) This gene encodes a protein that functions in the DNA double-strand break repair pathway choice, promoting non-homologous end joining (NHEJ) pathways, and limiting homologous recombination. This protein plays multiple roles in the DNA damage response, including promoting checkpoint signaling following DNA damage, acting as a scaffold for recruitment of DNA damage response proteins to damaged chromatin, and promoting NHEJ pathways by limiting end resection following a double-strand break. These roles are also important during V(D)J recombination, class switch recombination and at unprotected telomeres. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2017]

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.1817G>T	p.Arg606Leu	missense	Exon 16 of 18	NP_055259.2
	TP53BP1	NM_001141980.3	MANE Select	c.*3615C>A		3_prime_UTR	Exon 28 of 28	NP_001135452.1	Q12888-2
	TUBGCP4	NM_001286414.3		c.1820G>T	p.Arg607Leu	missense	Exon 16 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.1817G>T	p.Arg606Leu	missense	Exon 16 of 18	ENSP00000456648.2	Q9UGJ1-2
	TUBGCP4	ENST00000260383.11	TSL:1	c.1820G>T	p.Arg607Leu	missense	Exon 16 of 18	ENSP00000260383.7	Q9UGJ1-1
	TP53BP1	ENST00000382044.9	TSL:1 MANE Select	c.*3615C>A		3_prime_UTR	Exon 28 of 28	ENSP00000371475.5	Q12888-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461640 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727118

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.7	L
PhyloP100		9.9
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.20
Sift	Uncertain	0.022	D
Sift4G	Benign	0.66	T
Polyphen		0.045	B
Vest4		0.93
MutPred		0.56		Loss of solvent accessibility (P = 0.0155)
MVP		0.58
MPC		0.33
ClinPred		0.87	D
GERP RS		5.5
Varity_R		0.47
gMVP		0.55
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs769082991; hg19: chr15-43695966;