3-187236144-C-T

Variant names:

• chr3-187236144-C-T
• rs72549154
• NM_139125.4:c.1727G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_139125.4(MASP1):​c.1727G>A​(p.Arg576Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 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. R576M) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MASP1 NM_139125.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00400
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06375921).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MASP1	NM_139125.4	c.1727G>A	p.Arg576Lys	missense_variant	Exon 11 of 11	ENST00000296280.11	NP_624302.1
MASP1	NM_001879.6	c.1303+5337G>A		intron_variant	Intron 10 of 15	ENST00000337774.10	NP_001870.3
MASP1	NR_033519.2	n.1600G>A		non_coding_transcript_exon_variant	Exon 10 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MASP1	ENST00000296280.11	c.1727G>A	p.Arg576Lys	missense_variant	Exon 11 of 11	1	NM_139125.4	ENSP00000296280.7
MASP1	ENST00000337774.10	c.1303+5337G>A		intron_variant	Intron 10 of 15	1	NM_001879.6	ENSP00000336792.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461672 Hom.: 0 Cov.: 81 AF XY: 0.00 AC XY: 0 AN XY: 727162

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.78
DANN	Benign	0.87
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.064	T;T
MetaSVM	Benign	-0.74	T
PhyloP100		0.0040
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.26	N;N
REVEL	Benign	0.18
Sift	Benign	0.22	T;T
Sift4G	Benign	0.89	T;T
Polyphen		0.0010	B;B
Vest4		0.14
MutPred		0.50		Gain of methylation at R576 (P = 0.0061);.;
MVP		0.38
MPC		0.12
ClinPred		0.068	T
GERP RS		-0.34
gMVP		0.47
Mutation Taster		=88/12	polymorphism

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: rs72549154; hg19: chr3-186953932;