rs72550870

Positions:

chr1-11046609-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1PP3BP4_StrongBS1_SupportingBS2

The NM_006610.4(MASP2):c.359A>G(p.Asp120Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0265 in 1,613,734 control chromosomes in the GnomAD database, including 701 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.022 ( 51 hom., cov: 33)

Exomes 𝑓: 0.027 ( 650 hom. )

Consequence

MASP2
NM_006610.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1B:2

Conservation

PhyloP100: 7.73

Variant links:

Genes affected

MASP2 (HGNC:6902): (MBL associated serine protease 2) This gene encodes a member of the peptidase S1 family of serine proteases. The encoded preproprotein is proteolytically processed to generate A and B chains that heterodimerize to form the mature protease. This protease cleaves complement components C2 and C4 in order to generate C3 convertase in the lectin pathway of the complement system. The encoded protease also plays a role in the coagulation cascade through cleavage of prothrombin to form thrombin. Myocardial infarction and acute stroke patients exhibit reduced serum concentrations of the encoded protein. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

MASP2 links:

MASP2 (HGNC:):

MASP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity MASP2_HUMAN

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.010086238).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0221 (3368/152328) while in subpopulation NFE AF= 0.0324 (2204/68018). AF 95% confidence interval is 0.0313. There are 51 homozygotes in gnomad4. There are 1693 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 51 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MASP2	NM_006610.4 linkuse as main transcript	c.359A>G	p.Asp120Gly	missense_variant	3/11	ENST00000400897.8	NP_006601.2	O00187-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MASP2	ENST00000400897.8 linkuse as main transcript	c.359A>G	p.Asp120Gly	missense_variant	3/11	1	NM_006610.4	ENSP00000383690.3		O00187-1

Frequencies

GnomAD3 genomes

AF:

0.0221

AC:

3370

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00543

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0205

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0505

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0324

Gnomad OTH

AF:

0.0210

GnomAD3 exomes

AF:

0.0214

AC:

5366

AN:

250710

Hom.:

108

AF XY:

0.0212

AC XY:

2872

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.00438

Gnomad AMR exome

AF:

0.0103

Gnomad ASJ exome

AF:

0.00328

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00399

Gnomad FIN exome

AF:

0.0471

Gnomad NFE exome

AF:

0.0323

Gnomad OTH exome

AF:

0.0181

GnomAD4 exome

AF:

0.0270

AC:

39418

AN:

1461406

Hom.:

650

Cov.:

AF XY:

0.0264

AC XY:

19204

AN XY:

726988

show subpopulations

Gnomad4 AFR exome

AF:

0.00364

Gnomad4 AMR exome

AF:

0.0106

Gnomad4 ASJ exome

AF:

0.00360

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00423

Gnomad4 FIN exome

AF:

0.0463

Gnomad4 NFE exome

AF:

0.0310

Gnomad4 OTH exome

AF:

0.0237

GnomAD4 genome

AF:

0.0221

AC:

3368

AN:

152328

Hom.:

Cov.:

AF XY:

0.0227

AC XY:

1693

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00541

Gnomad4 AMR

AF:

0.0205

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.0505

Gnomad4 NFE

AF:

0.0324

Gnomad4 OTH

AF:

0.0208

Alfa

AF:

0.0257

Hom.:

Bravo

AF:

0.0189

TwinsUK

AF:

0.0186

AC:

ALSPAC

AF:

0.0257

AC:

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.0288

AC:

248

ExAC

AF:

0.0222

AC:

2692

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0265

EpiControl

AF:

0.0268

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Immunodeficiency due to MASP-2 deficiency

Pathogenic:3Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jun 15, 2021	MASP2 NM_006610.3 exon 3 p.Asp120Gly (c.359A>G): This variant has been reported in the literature in multiple individuals with a broad spectrum of immunodeficiency and autoimmune phenotypes in the heterozygous and homozygous state (Stengaard-Pedersen 2003 PMID:12904520, Schafranski 2008 PMID:18295674, Swierzko 2009 PMID:19307021, Goeldner 2014 PMID:24632598, Olszowski 2014 PMID:24332888, Rodriguez-Flores 2014 PMID:24123366, Garcia Laorden 2020 PMID:31828694). However, numerous individuals with this variant have been reported to be clinically unaffected and this variant is present in 5% (536/10618) of Finnish alleles including 8 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-11046609-T-C?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:5210). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies support that this variant will impact the protein resulting in MASP2 deficiency (Thiel 2009 PMID:19234189, Valles 2009 PMID:19775369). However, these studies may not accurately represent in vivo biological function. Overall, data on this variant supports an association to MASP2 deficiency but it is unclear whether MASP2 deficiency has a clinical impact. This uncertainty, as well as the very high minor allele frequency suggests that this variant may be more accurately classified as a risk allele vs. a mendelian disease variant. -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"	May 01, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 07, 2003	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 20, 2017	The MASP2 c.359A>G (p.Asp120Gly) missense variant has been reported in two studies in which it is described in a homozygous state in two individuals with recurrent infections and low serum MASP2 levels (Stengaard-Pedersen et al. 2003; Cedzynski et al. 2004). Additional family members who were heterozygous for the variant were found to have low serum MASP2 concentrations but no clinical symptoms. The p.Asp120Gly variant has also been investigated in healthy unrelated individuals from different populations. Four individuals were found to carry the p.Asp120Gly variant in a homozygous state and have MASP2 deficiency but show no clinical symptoms (GarcÃa-Laorden et al. 2006; Olszowski et al. 2014; Sokolowska et al. 2015). Functional studies by Stengaard-Pedersen et al. (2003) and Thiel et al. (2009) demonstrated that the p.Asp120Gly variant had a reduced capacity to activate complement through the MBL-initiated classical pathway. While the allele frequency for the p.Asp120Gly variant appears to be high at 0.0479 in the European (Finnish) population of the Exome Aggregation Consortium, studies have shown an over-representation of this variant in individuals with low levels of MASP2 as compared to controls. Many individuals who carry variants classified as pathogenic in MASP2 never experience clinical symptoms, and therefore this variant is thought to confer a mildly elevated risk for infection and inflammatory diseases. Based on the evidence, the p.Asp120Gly variant is classified as likely pathogenic for MASP2 deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Nov 03, 2021

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Nov 11, 2015

- -

MASP2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.38

MutationAssessor

Pathogenic

3.6

H;H

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-6.6

D;D

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.98

D;D

Vest4

0.32

MPC

0.29

ClinPred

0.052

GERP RS

4.8

Varity_R

0.95

gMVP

0.87

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