NM_139125.4:c.1277G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_139125.4(MASP1):c.1277G>A(p.Gly426Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,613,460 control chromosomes in the GnomAD database, including 234 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 13 hom., cov: 32)

Exomes 𝑓: 0.016 ( 221 hom. )

Consequence

MASP1
NM_139125.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.07

Publications

13 publications found

Variant links:

Genes affected

MASP1 (HGNC:6901): (MBL associated serine protease 1) This gene encodes a serine protease that functions as a component of the lectin pathway of complement activation. The complement pathway plays an essential role in the innate and adaptive immune response. The encoded protein is synthesized as a zymogen and is activated when it complexes with the pathogen recognition molecules of lectin pathway, the mannose-binding lectin and the ficolins. This protein is not directly involved in complement activation but may play a role as an amplifier of complement activation by cleaving complement C2 or by activating another complement serine protease, MASP-2. The encoded protein is also able to cleave fibrinogen and factor XIII and may may be involved in coagulation. A splice variant of this gene which lacks the serine protease domain functions as an inhibitor of the complement pathway. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

MASP1 Gene-Disease associations (from GenCC):

3MC syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
3MC syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MASP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043150485).

BP6

Variant 3-187241507-C-T is Benign according to our data. Variant chr3-187241507-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 463034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0121 (1836/152100) while in subpopulation NFE AF = 0.0178 (1208/67984). AF 95% confidence interval is 0.0169. There are 13 homozygotes in GnomAd4. There are 876 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MASP1	NM_139125.4 link	c.1277G>A	p.Gly426Glu	missense_variant	Exon 10 of 11	ENST00000296280.11	NP_624302.1
MASP1	NM_001879.6 link	c.1277G>A	p.Gly426Glu	missense_variant	Exon 10 of 16	ENST00000337774.10	NP_001870.3
MASP1	NR_033519.2 link	n.1150G>A		non_coding_transcript_exon_variant	Exon 9 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MASP1	ENST00000296280.11 link	c.1277G>A	p.Gly426Glu	missense_variant	Exon 10 of 11	1	NM_139125.4	ENSP00000296280.7
MASP1	ENST00000337774.10 link	c.1277G>A	p.Gly426Glu	missense_variant	Exon 10 of 16	1	NM_001879.6	ENSP00000336792.5

Frequencies

GnomAD3 genomes

AF:

0.0121

AC:

1836

AN:

151982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00302

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0136

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.0227

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0178

Gnomad OTH

AF:

0.0167

GnomAD2 exomes

AF:

0.0122

AC:

3072

AN:

251482

AF XY:

0.0122

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.00934

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0236

Gnomad NFE exome

AF:

0.0180

Gnomad OTH exome

AF:

0.0143

GnomAD4 exome

AF:

0.0163

AC:

23840

AN:

1461360

Hom.:

221

Cov.:

AF XY:

0.0157

AC XY:

11429

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.00218

AC:

AN:

33470

American (AMR)

AF:

0.0103

AC:

462

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00142

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00179

AC:

154

AN:

86248

European-Finnish (FIN)

AF:

0.0217

AC:

1160

AN:

53412

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0191

AC:

21185

AN:

1111526

Other (OTH)

AF:

0.0125

AC:

752

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

1077

2155

3232

4310

5387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

798

1596

2394

3192

3990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0121

AC:

1836

AN:

152100

Hom.:

Cov.:

AF XY:

0.0118

AC XY:

876

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00301

AC:

125

AN:

41488

American (AMR)

AF:

0.0136

AC:

208

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00270

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0227

AC:

241

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0178

AC:

1208

AN:

67984

Other (OTH)

AF:

0.0166

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

186

278

371

464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0142

Hom.:

Bravo

AF:

0.0107

TwinsUK

AF:

0.0213

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0144

AC:

124

ExAC

AF:

0.0118

AC:

1432

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

3MC syndrome 1

Benign:2

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 16, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.23

DEOGEN2

Benign

0.15

T;.;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.51

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.68

T;T;T

MetaRNN

Benign

0.0043

T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.1

M;M;.

PhyloP100

2.1

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.6

D;N;D

REVEL

Benign

0.22

Sift

Benign

0.89

T;T;T

Sift4G

Benign

0.37

T;T;T

Polyphen

0.15

B;B;B

Vest4

0.20

MPC

0.18

ClinPred

0.037

GERP RS

3.1

Varity_R

0.37

gMVP

0.49

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over