5-160428637-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_004219.4(PTTG1):c.565C>T(p.Leu189=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,614,014 control chromosomes in the GnomAD database, including 209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (105 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (104 hom.)
• Consequence: PTTG1 NM_004219.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.425

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 5-160428637-C-T is Benign according to our data. Variant chr5-160428637-C-T is described in ClinVar as [Benign]. Clinvar id is 790985.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.425 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTTG1	NM_004219.4	c.565C>T	p.Leu189=	synonymous_variant	6/6	ENST00000352433.10
PTTG1	NM_001282382.1	c.565C>T	p.Leu189=	synonymous_variant	5/5
PTTG1	NM_001282383.1	c.565C>T	p.Leu189=	synonymous_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTTG1	ENST00000352433.10	c.565C>T	p.Leu189=	synonymous_variant	6/6	1	NM_004219.4	P1
PTTG1	ENST00000393964.1	c.565C>T	p.Leu189=	synonymous_variant	5/5	1		P1
PTTG1	ENST00000520452.5	c.565C>T	p.Leu189=	synonymous_variant	6/6	3		P1
PTTG1	ENST00000519287.1	n.568C>T		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.0200 AC: 3041 AN: 152174 Hom.: 105 Cov.: 33

Gnomad AFR AF: 0.0700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00739

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00530 AC: 1332 AN: 251430 Hom.: 33 AF XY: 0.00392 AC XY: 533 AN XY: 135886

Gnomad AFR exome AF: 0.0717

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00209 AC: 3056 AN: 1461722 Hom.: 104 Cov.: 30 AF XY: 0.00182 AC XY: 1327 AN XY: 727170

Gnomad4 AFR exome AF: 0.0749

Gnomad4 AMR exome AF: 0.00411

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.00442

GnomAD4 genome AF: 0.0200 AC: 3044 AN: 152292 Hom.: 105 Cov.: 33 AF XY: 0.0190 AC XY: 1412 AN XY: 74466

Gnomad4 AFR AF: 0.0699

Gnomad4 AMR AF: 0.00738

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.0105 Hom.: 24

Bravo AF: 0.0226

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	8.5
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs7335; hg19: chr5-159855644;