Variant 1-176556834-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020318.3(PAPPA2):c.512C>G(p.Thr171Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,613,962 control chromosomes in the GnomAD database, including 204 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.021 ( 108 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 96 hom. )

Consequence

PAPPA2
NM_020318.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.38

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026737154).

BP6

Variant 1-176556834-C-G is Benign according to our data. Variant chr1-176556834-C-G is described in ClinVar as [Benign]. Clinvar id is 784962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0702 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAPPA2	NM_020318.3 linkuse as main transcript	c.512C>G	p.Thr171Ser	missense_variant	2/23	ENST00000367662.5	NP_064714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAPPA2	ENST00000367662.5 linkuse as main transcript	c.512C>G	p.Thr171Ser	missense_variant	2/23	1	NM_020318.3	ENSP00000356634	P1	Q9BXP8-1
PAPPA2	ENST00000367661.7 linkuse as main transcript	c.512C>G	p.Thr171Ser	missense_variant	2/5	1		ENSP00000356633		Q9BXP8-2

Frequencies

GnomAD3 genomes

AF:

0.0211

AC:

3206

AN:

152014

Hom.:

107

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00773

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00746

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.00640

AC:

1592

AN:

248752

Hom.:

AF XY:

0.00578

AC XY:

781

AN XY:

135008

show subpopulations

Gnomad AFR exome

AF:

0.0705

Gnomad AMR exome

AF:

0.00411

Gnomad ASJ exome

AF:

0.0000996

Gnomad EAS exome

AF:

0.00150

Gnomad SAS exome

AF:

0.00931

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000284

Gnomad OTH exome

AF:

0.00265

GnomAD4 exome

AF:

0.00277

AC:

4042

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00277

AC XY:

2012

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0733

Gnomad4 AMR exome

AF:

0.00411

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000932

Gnomad4 SAS exome

AF:

0.00886

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000237

Gnomad4 OTH exome

AF:

0.00508

GnomAD4 genome

AF:

0.0211

AC:

3212

AN:

152132

Hom.:

108

Cov.:

AF XY:

0.0202

AC XY:

1504

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0724

Gnomad4 AMR

AF:

0.00765

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00685

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.00338

Hom.:

Bravo

AF:

0.0229

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.0624

AC:

258

ESP6500EA

AF:

0.000357

AC:

ExAC

AF:

0.00750

AC:

907

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.75

CADD

Benign

7.0

DANN

Benign

0.80

DEOGEN2

Benign

0.044

.;T

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.26

T;T

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.16

N;N

REVEL

Benign

0.079

Sift

Benign

0.40

T;T

Sift4G

Benign

0.36

T;T

Polyphen

0.0020

.;B

Vest4

0.064

MutPred

0.11

Loss of helix (P = 0.079);Loss of helix (P = 0.079);

MVP

0.37

MPC

0.15

ClinPred

0.0048

GERP RS

4.1

Varity_R

0.053

gMVP

0.11

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over