5-160427719-T-A

Variant summary

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

The NM_004219.4(PTTG1):c.375T>A(p.Phe125Leu) variant causes a missense change involving the alteration of a non-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: 33)
• Consequence: PTTG1 NM_004219.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

Genes affected

PTTG1 (HGNC:9690): (PTTG1 regulator of sister chromatid separation, securin) The encoded protein is a homolog of yeast securin proteins, which prevent separins from promoting sister chromatid separation. It is an anaphase-promoting complex (APC) substrate that associates with a separin until activation of the APC. The gene product has transforming activity in vitro and tumorigenic activity in vivo, and the gene is highly expressed in various tumors. The gene product contains 2 PXXP motifs, which are required for its transforming and tumorigenic activities, as well as for its stimulation of basic fibroblast growth factor expression. It also contains a destruction box (D box) that is required for its degradation by the APC. The acidic C-terminal region of the encoded protein can act as a transactivation domain. The gene product is mainly a cytosolic protein, although it partially localizes in the nucleus. Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2013]

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, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTTG1	NM_004219.4	c.375T>A	p.Phe125Leu	missense_variant	5/6	ENST00000352433.10
PTTG1	NM_001282382.1	c.375T>A	p.Phe125Leu	missense_variant	4/5
PTTG1	NM_001282383.1	c.375T>A	p.Phe125Leu	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTTG1	ENST00000352433.10	c.375T>A	p.Phe125Leu	missense_variant	5/6	1	NM_004219.4	P1
PTTG1	ENST00000393964.1	c.375T>A	p.Phe125Leu	missense_variant	4/5	1		P1
PTTG1	ENST00000520452.5	c.375T>A	p.Phe125Leu	missense_variant	5/6	3		P1
PTTG1	ENST00000519287.1	n.378T>A		non_coding_transcript_exon_variant	5/6	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2023

The c.375T>A (p.F125L) alteration is located in exon 5 (coding exon 4) of the PTTG1 gene. This alteration results from a T to A substitution at nucleotide position 375, causing the phenylalanine (F) at amino acid position 125 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;T;T
Eigen	Benign	-0.056
Eigen_PC	Benign	-0.097
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	0.75	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Uncertain	0.30
Sift	Benign	0.070	T;T;T
Sift4G	Benign	0.087	T;T;T
Polyphen		0.91	P;P;P
Vest4		0.84
MutPred		0.69		Gain of disorder (P = 0.1722);Gain of disorder (P = 0.1722);Gain of disorder (P = 0.1722);
MVP		0.61
MPC		1.0
ClinPred		0.99	D
GERP RS		0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-159854726;