rs72550870

Variant names:

• chr1-11046609-T-C
• rs72550870
• NM_006610.4:c.359A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP4_Strong BS1_Supporting BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2 B:3
• Conservation: PhyloP100: 7.73
• Publications: 66 publications found

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 Gene-Disease associations (from GenCC):

• immunodeficiency due to MASP-2 deficiency

  Inheritance: AR Classification: STRONG Submitted by: Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. 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 rank	MANE	Protein	UniProt
MASP2	NM_006610.4	c.359A>G	p.Asp120Gly	missense_variant	Exon 3 of 11	ENST00000400897.8	NP_006601.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MASP2	ENST00000400897.8	c.359A>G	p.Asp120Gly	missense_variant	Exon 3 of 11	1	NM_006610.4	ENSP00000383690.3

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3370 AN: 152210 Hom.: 51 Cov.: 33

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

GnomAD2 exomes AF: 0.0214 AC: 5366 AN: 250710 AF XY: 0.0212

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 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.: 32 AF XY: 0.0264 AC XY: 19204 AN XY: 726988

African (AFR) AF: 0.00364 AC: 122 AN: 33480

American (AMR) AF: 0.0106 AC: 475 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00360 AC: 94 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00423 AC: 365 AN: 86250

European-Finnish (FIN) AF: 0.0463 AC: 2453 AN: 52998

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.0310 AC: 34458 AN: 1111964

Other (OTH) AF: 0.0237 AC: 1432 AN: 60390

GnomAD4 genome AF: 0.0221 AC: 3368 AN: 152328 Hom.: 51 Cov.: 33 AF XY: 0.0227 AC XY: 1693 AN XY: 74494

African (AFR) AF: 0.00541 AC: 225 AN: 41588

American (AMR) AF: 0.0205 AC: 314 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4830

European-Finnish (FIN) AF: 0.0505 AC: 536 AN: 10618

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0324 AC: 2204 AN: 68018

Other (OTH) AF: 0.0208 AC: 44 AN: 2116

Alfa AF: 0.0285 Hom.: 138

Bravo AF: 0.0189

TwinsUK AF: 0.0186 AC: 69

ALSPAC AF: 0.0257 AC: 99

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0288 AC: 248

ExAC AF: 0.0222 AC: 2692

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0265

EpiControl AF: 0.0268

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency due to MASP-2 deficiency Pathogenic:3 Uncertain:2

Oct 20, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (García-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. -

May 01, 2022

Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 07, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 15, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 04, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not specified Benign:2

Nov 11, 2015

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Nov 03, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MASP2-related disorder Benign:1

Sep 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	T
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Pathogenic	3.6	H;H
PhyloP100		7.7
PrimateAI	Uncertain	0.55	T
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	T
GERP RS		4.8
Varity_R		0.95
gMVP		0.87
Mutation Taster		=44/56	disease causing (ClinVar)

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: rs72550870; hg19: chr1-11106666; COSMIC: COSV68896437; COSMIC: COSV68896437;