rs10489478

Variant names:

• chr1-176597214-C-T
• rs10489478
• NM_020318.3:c.1991+1619C>T

Variant summary

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

The NM_020318.3(PAPPA2):​c.1991+1619C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 152,114 control chromosomes in the GnomAD database, including 2,211 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 (2211 hom., cov: 32)
• Consequence: PAPPA2 NM_020318.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.713
• 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: 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=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.186 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.1991+1619C>T		intron	N/A	NP_064714.2
	PAPPA2	NM_021936.3		c.1991+1619C>T		intron	N/A	NP_068755.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPPA2	ENST00000367662.5	TSL:1 MANE Select	c.1991+1619C>T		intron	N/A	ENSP00000356634.3
	PAPPA2	ENST00000367661.7	TSL:1	c.1991+1619C>T		intron	N/A	ENSP00000356633.3

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25260 AN: 151996 Hom.: 2212 Cov.: 32

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.177

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

GnomAD4 genome AF: 0.166 AC: 25255 AN: 152114 Hom.: 2211 Cov.: 32 AF XY: 0.165 AC XY: 12278 AN XY: 74358

African (AFR) AF: 0.164 AC: 6801 AN: 41486

American (AMR) AF: 0.134 AC: 2047 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 802 AN: 3468

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5186

South Asian (SAS) AF: 0.196 AC: 945 AN: 4816

European-Finnish (FIN) AF: 0.180 AC: 1905 AN: 10564

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

European-Non Finnish (NFE) AF: 0.177 AC: 12046 AN: 67990

Other (OTH) AF: 0.175 AC: 368 AN: 2108

Alfa AF: 0.174 Hom.: 1367

Bravo AF: 0.162

Asia WGS AF: 0.0920 AC: 321 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.7
DANN	Benign	0.78
PhyloP100		-0.71
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: rs10489478; hg19: chr1-176566350;