Genetic Variant MASP1:p.Arg288Leu (chr3-187253197-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_139125.4(MASP1):c.863G>T(p.Arg288Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R288Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

MASP1
NM_139125.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.89

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21844804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MASP1	NM_139125.4 link	c.863G>T	p.Arg288Leu	missense_variant	Exon 6 of 11	ENST00000296280.11	NP_624302.1
MASP1	NM_001879.6 link	c.863G>T	p.Arg288Leu	missense_variant	Exon 6 of 16	ENST00000337774.10	NP_001870.3
MASP1	NM_001031849.3 link	c.863G>T	p.Arg288Leu	missense_variant	Exon 6 of 9		NP_001027019.1
MASP1	NR_033519.2 link	n.736G>T		non_coding_transcript_exon_variant	Exon 5 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MASP1	ENST00000296280.11 link	c.863G>T	p.Arg288Leu	missense_variant	Exon 6 of 11	1	NM_139125.4	ENSP00000296280.7
MASP1	ENST00000337774.10 link	c.863G>T	p.Arg288Leu	missense_variant	Exon 6 of 16	1	NM_001879.6	ENSP00000336792.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

T;.;.;.;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.57

LIST_S2

Uncertain

0.90

D;D;D;D;D

M_CAP

Benign

0.0046

MetaRNN

Benign

0.22

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.72

N;N;.;N;.

PhyloP100

1.9

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.7

N;N;D;N;N

REVEL

Benign

0.066

Sift

Benign

0.25

T;T;T;T;T

Sift4G

Benign

0.33

T;T;T;T;T

Polyphen

0.029

B;B;B;B;B

Vest4

0.18

MutPred

0.67

Gain of glycosylation at S293 (P = 0.0074);Gain of glycosylation at S293 (P = 0.0074);.;Gain of glycosylation at S293 (P = 0.0074);.;

MVP

0.27

MPC

0.15

ClinPred

0.31

GERP RS

2.0

Varity_R

0.22

gMVP

0.53

Mutation Taster

=68/32

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over