5-160427824-G-C

Position:

• chr5-160427824-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_004219.4(PTTG1):​c.480G>C​(p.Gln160His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PTTG1 NM_004219.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.541

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]

PTTG1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042192012).
• BP6: Variant 5-160427824-G-C is Benign according to our data. Variant chr5-160427824-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3311704.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTTG1	NM_004219.4	c.480G>C	p.Gln160His	missense_variant	5/6	ENST00000352433.10	NP_004210.1
PTTG1	NM_001282382.1	c.480G>C	p.Gln160His	missense_variant	4/5		NP_001269311.1
PTTG1	NM_001282383.1	c.480G>C	p.Gln160His	missense_variant	5/6		NP_001269312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTTG1	ENST00000352433.10	c.480G>C	p.Gln160His	missense_variant	5/6	1	NM_004219.4	ENSP00000344936.5
PTTG1	ENST00000393964.1	c.480G>C	p.Gln160His	missense_variant	4/5	1		ENSP00000377536.1
PTTG1	ENST00000520452.5	c.480G>C	p.Gln160His	missense_variant	5/6	3		ENSP00000430642.1
PTTG1	ENST00000519287.1	n.483G>C		non_coding_transcript_exon_variant	5/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.3
DANN	Benign	0.74
DEOGEN2	Benign	0.070	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.51	.;.;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.63	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.080	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.55	T;T;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.13
MutPred		0.40		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.23
MPC		0.26
ClinPred		0.025	T
GERP RS		-2.6
Varity_R		0.021
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr5-159854831;