5-160422579-A-G

Variant names:

• chr5-160422579-A-G
• rs1895320
• NM_004219.4:c.92-130A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004219.4(PTTG1):​c.92-130A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,115,174 control chromosomes in the GnomAD database, including 12,524 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (1547 hom., cov: 32)
  • Exomes 𝑓: 0.15 (10977 hom.)
• Consequence: PTTG1 NM_004219.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.42
• Publications: 19 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTTG1	NM_004219.4	c.92-130A>G		intron_variant	Intron 2 of 5	ENST00000352433.10	NP_004210.1
PTTG1	NM_001282382.1	c.92-130A>G		intron_variant	Intron 1 of 4		NP_001269311.1
PTTG1	NM_001282383.1	c.92-130A>G		intron_variant	Intron 2 of 5		NP_001269312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTTG1	ENST00000352433.10	c.92-130A>G		intron_variant	Intron 2 of 5	1	NM_004219.4	ENSP00000344936.5

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21289 AN: 151998 Hom.: 1547 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.0988

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.156

GnomAD2 exomes AF: 0.151 AC: 28819 AN: 190454 AF XY: 0.157

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.0755

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.214

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.148

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.147 AC: 141465 AN: 963058 Hom.: 10977 Cov.: 13 AF XY: 0.150 AC XY: 74269 AN XY: 495624

African (AFR) AF: 0.123 AC: 2832 AN: 23088

American (AMR) AF: 0.0807 AC: 3067 AN: 38016

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 4045 AN: 22766

East Asian (EAS) AF: 0.175 AC: 6199 AN: 35466

South Asian (SAS) AF: 0.201 AC: 14675 AN: 73160

European-Finnish (FIN) AF: 0.154 AC: 7920 AN: 51308

Middle Eastern (MID) AF: 0.200 AC: 975 AN: 4868

European-Non Finnish (NFE) AF: 0.142 AC: 95156 AN: 670526

Other (OTH) AF: 0.150 AC: 6596 AN: 43860

GnomAD4 genome AF: 0.140 AC: 21297 AN: 152116 Hom.: 1547 Cov.: 32 AF XY: 0.140 AC XY: 10404 AN XY: 74366

African (AFR) AF: 0.123 AC: 5084 AN: 41496

American (AMR) AF: 0.0987 AC: 1508 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 562 AN: 3470

East Asian (EAS) AF: 0.201 AC: 1042 AN: 5174

South Asian (SAS) AF: 0.196 AC: 943 AN: 4822

European-Finnish (FIN) AF: 0.154 AC: 1627 AN: 10570

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9920 AN: 67982

Other (OTH) AF: 0.155 AC: 328 AN: 2110

Alfa AF: 0.145 Hom.: 3315

Bravo AF: 0.135

Asia WGS AF: 0.200 AC: 699 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.3
DANN	Benign	0.40
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs1895320; hg19: chr5-159849586; COSMIC: COSV107382266; COSMIC: COSV107382266;