rs4507975

Variant names:

• chr1-176715296-A-G
• rs4507975
• NM_020318.3:c.3798+3315A>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.3798+3315A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 152,072 control chromosomes in the GnomAD database, including 8,264 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 0.32 (8264 hom., cov: 32)
• Consequence: PAPPA2 NM_020318.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.222
• Publications: 8 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPPA2	NM_020318.3	c.3798+3315A>G		intron_variant	Intron 12 of 22	ENST00000367662.5	NP_064714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPPA2	ENST00000367662.5	c.3798+3315A>G		intron_variant	Intron 12 of 22	1	NM_020318.3	ENSP00000356634.3

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48624 AN: 151954 Hom.: 8249 Cov.: 32

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.360

Gnomad EAS AF: 0.0821

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.327

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

GnomAD4 genome AF: 0.320 AC: 48687 AN: 152072 Hom.: 8264 Cov.: 32 AF XY: 0.320 AC XY: 23777 AN XY: 74354

African (AFR) AF: 0.416 AC: 17242 AN: 41450

American (AMR) AF: 0.236 AC: 3611 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.360 AC: 1248 AN: 3468

East Asian (EAS) AF: 0.0829 AC: 429 AN: 5176

South Asian (SAS) AF: 0.344 AC: 1655 AN: 4816

European-Finnish (FIN) AF: 0.344 AC: 3637 AN: 10578

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.292 AC: 19819 AN: 67976

Other (OTH) AF: 0.324 AC: 685 AN: 2112

Alfa AF: 0.295 Hom.: 21988

Bravo AF: 0.312

Asia WGS AF: 0.212 AC: 740 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.3
DANN	Benign	0.44
PhyloP100		0.22
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: rs4507975; hg19: chr1-176684432;