rs4921281

Variant names:

• chr5-160424047-A-C
• rs4921281
• NM_004219.4:c.277-190A>C

Variant summary

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

The NM_004219.4(PTTG1):​c.277-190A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 152,230 control chromosomes in the GnomAD database, including 1,307 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 0.13 (1307 hom., cov: 33)
• Consequence: PTTG1 NM_004219.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22
• Publications: 5 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004219.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTTG1	NM_004219.4	MANE Select	c.277-190A>C		intron	N/A	NP_004210.1
	PTTG1	NM_001282382.1		c.277-190A>C		intron	N/A	NP_001269311.1
	PTTG1	NM_001282383.1		c.277-190A>C		intron	N/A	NP_001269312.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTTG1	ENST00000352433.10	TSL:1 MANE Select	c.277-190A>C		intron	N/A	ENSP00000344936.5
	PTTG1	ENST00000393964.1	TSL:1	c.277-190A>C		intron	N/A	ENSP00000377536.1
	PTTG1	ENST00000520452.5	TSL:3	c.277-190A>C		intron	N/A	ENSP00000430642.1

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19306 AN: 152112 Hom.: 1307 Cov.: 33

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.0911

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.137

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.127 AC: 19311 AN: 152230 Hom.: 1307 Cov.: 33 AF XY: 0.124 AC XY: 9237 AN XY: 74434

African (AFR) AF: 0.127 AC: 5260 AN: 41536

American (AMR) AF: 0.0909 AC: 1391 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 456 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5190

South Asian (SAS) AF: 0.101 AC: 487 AN: 4828

European-Finnish (FIN) AF: 0.150 AC: 1589 AN: 10590

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9559 AN: 68006

Other (OTH) AF: 0.136 AC: 286 AN: 2110

Alfa AF: 0.136 Hom.: 822

Bravo AF: 0.124

Asia WGS AF: 0.0570 AC: 203 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	12
DANN	Benign	0.72
PhyloP100		1.2
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: rs4921281; hg19: chr5-159851054;