rs377074720

Positions:

chr3-187236295-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_139125.4(MASP1):c.1576C>T(p.Arg526*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,614,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

MASP1
NM_139125.4 stop_gained

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.635

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 links:

MASP1 (HGNC:):

MASP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.279 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-187236295-G-A is Pathogenic according to our data. Variant chr3-187236295-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191186.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MASP1	NM_139125.4 linkuse as main transcript	c.1576C>T	p.Arg526*	stop_gained	11/11	ENST00000296280.11	NP_624302.1	P48740-2
MASP1	NM_001879.6 linkuse as main transcript	c.1303+5186C>T		intron_variant		ENST00000337774.10	NP_001870.3	P48740-1
MASP1	NR_033519.2 linkuse as main transcript	n.1449C>T		non_coding_transcript_exon_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MASP1	ENST00000296280.11 linkuse as main transcript	c.1576C>T	p.Arg526*	stop_gained	11/11	1	NM_139125.4	ENSP00000296280.7		P48740-2
MASP1	ENST00000337774.10 linkuse as main transcript	c.1303+5186C>T		intron_variant		1	NM_001879.6	ENSP00000336792.5		P48740-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251270

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000956

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

3MC syndrome 1

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained variant c.1576C>T p.Arg526Ter in the MASP1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.004% in the gnomAD Exomes. It has been submitted to ClinVar as Likely Pathogenic/ Uncertain significance. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing Degn et al., 2012. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Sep 14, 2018	- -

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, flagged submission	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2020	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 203 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27124789) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.94

Vest4

0.89

GERP RS

4.1

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