1-176823113-A-G

Variant names:

• chr1-176823113-A-G
• rs1325598
• NM_020318.3:c.5203-17060A>G

Variant summary

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

The NM_020318.3(PAPPA2):​c.5203-17060A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.615 in 152,108 control chromosomes in the GnomAD database, including 29,390 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 0.62 (29390 hom., cov: 33)
• Consequence: PAPPA2 NM_020318.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 32 publications found

Genes affected

PAPPA2 (HGNC:14615): (pappalysin 2) This gene encodes a member of the pappalysin family of metzincin metalloproteinases. The encoded protein cleaves insulin-like growth factor-binding protein 5 and is thought to be a local regulator of insulin-like growth factor (IGF) bioavailability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2010]

PAPPA2 Gene-Disease associations (from GenCC):

• Short stature, Dauber-Argente type

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.736 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020318.3. 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
	PAPPA2	NM_020318.3	MANE Select	c.5203-17060A>G		intron	N/A	NP_064714.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPPA2	ENST00000367662.5	TSL:1 MANE Select	c.5203-17060A>G		intron	N/A	ENSP00000356634.3
	PAPPA2	ENST00000479836.1	TSL:3	n.221-13522A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.615 AC: 93545 AN: 151992 Hom.: 29369 Cov.: 33

Gnomad AFR AF: 0.736

Gnomad AMI AF: 0.645

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.756

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.555

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.566

Gnomad OTH AF: 0.592

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

GnomAD4 genome AF: 0.615 AC: 93615 AN: 152108 Hom.: 29390 Cov.: 33 AF XY: 0.612 AC XY: 45490 AN XY: 74350

African (AFR) AF: 0.736 AC: 30528 AN: 41494

American (AMR) AF: 0.576 AC: 8810 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1643 AN: 3472

East Asian (EAS) AF: 0.756 AC: 3918 AN: 5182

South Asian (SAS) AF: 0.487 AC: 2349 AN: 4820

European-Finnish (FIN) AF: 0.555 AC: 5869 AN: 10572

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.566 AC: 38498 AN: 67962

Other (OTH) AF: 0.597 AC: 1263 AN: 2114

Alfa AF: 0.583 Hom.: 77176

Bravo AF: 0.624

Asia WGS AF: 0.643 AC: 2236 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.13
DANN	Benign	0.38
PhyloP100		-1.3
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: rs1325598; hg19: chr1-176792249;