rs10913237

Variant names:

• chr1-176661280-G-A
• rs10913237
• NM_020318.3:c.1992-9690G>A

Variant summary

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

The NM_020318.3(PAPPA2):​c.1992-9690G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 151,846 control chromosomes in the GnomAD database, including 2,464 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 0.17 (2464 hom., cov: 31)
• Consequence: PAPPA2 NM_020318.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.455
• Publications: 3 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.192 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPPA2	NM_020318.3	MANE Select	c.1992-9690G>A		intron	N/A	NP_064714.2	Q9BXP8-1
	PAPPA2	NM_021936.3		c.1992-9690G>A		intron	N/A	NP_068755.2	Q9BXP8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPPA2	ENST00000367662.5	TSL:1 MANE Select	c.1992-9690G>A		intron	N/A	ENSP00000356634.3	Q9BXP8-1
	PAPPA2	ENST00000367661.7	TSL:1	c.1992-9690G>A		intron	N/A	ENSP00000356633.3	Q9BXP8-2

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26499 AN: 151728 Hom.: 2463 Cov.: 31

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.00252

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.183

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

GnomAD4 genome AF: 0.175 AC: 26502 AN: 151846 Hom.: 2464 Cov.: 31 AF XY: 0.172 AC XY: 12793 AN XY: 74176

African (AFR) AF: 0.196 AC: 8113 AN: 41404

American (AMR) AF: 0.135 AC: 2053 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 800 AN: 3466

East Asian (EAS) AF: 0.00272 AC: 14 AN: 5148

South Asian (SAS) AF: 0.194 AC: 933 AN: 4818

European-Finnish (FIN) AF: 0.180 AC: 1891 AN: 10528

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.177 AC: 11993 AN: 67942

Other (OTH) AF: 0.181 AC: 380 AN: 2104

Alfa AF: 0.179 Hom.: 1332

Bravo AF: 0.171

Asia WGS AF: 0.0940 AC: 328 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.70
DANN	Benign	0.80
PhyloP100		-0.46
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: rs10913237; hg19: chr1-176630416;