rs10454444

Variant names:

• chr1-176680045-T-C
• rs10454444
• NM_020318.3:c.2137+8930T>C

Variant summary

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

The NM_020318.3(PAPPA2):​c.2137+8930T>C 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 152,154 control chromosomes in the GnomAD database, including 2,483 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 (2483 hom., cov: 32)
• Consequence: PAPPA2 NM_020318.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0550
• Publications: 1 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPPA2	NM_020318.3	c.2137+8930T>C		intron_variant	Intron 4 of 22	ENST00000367662.5	NP_064714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPPA2	ENST00000367662.5	c.2137+8930T>C		intron_variant	Intron 4 of 22	1	NM_020318.3	ENSP00000356634.3
PAPPA2	ENST00000367661.7	c.2137+8930T>C		intron_variant	Intron 4 of 4	1		ENSP00000356633.3

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26584 AN: 152036 Hom.: 2482 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.177

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: 26587 AN: 152154 Hom.: 2483 Cov.: 32 AF XY: 0.173 AC XY: 12856 AN XY: 74370

African (AFR) AF: 0.196 AC: 8149 AN: 41502

American (AMR) AF: 0.135 AC: 2061 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 800 AN: 3468

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5182

South Asian (SAS) AF: 0.194 AC: 934 AN: 4824

European-Finnish (FIN) AF: 0.181 AC: 1913 AN: 10582

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

European-Non Finnish (NFE) AF: 0.177 AC: 12011 AN: 68008

Other (OTH) AF: 0.181 AC: 381 AN: 2110

Alfa AF: 0.177 Hom.: 3255

Bravo AF: 0.172

Asia WGS AF: 0.0930 AC: 326 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.1
DANN	Benign	0.38
PhyloP100		0.055
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10454444; hg19: chr1-176649181;