3-187236144-C-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139125.4(MASP1):​c.1727G>T​(p.Arg576Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 1,613,940 control chromosomes in the GnomAD database, including 2,259 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (608 hom., cov: 33)
  • Exomes 𝑓: 0.040 (1651 hom.)
• Consequence: MASP1 NM_139125.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00400
• Publications: 12 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020614266).
• BP6: Variant 3-187236144-C-A is Benign according to our data. Variant chr3-187236144-C-A is described in ClinVar as Benign. ClinVar VariationId is 1166550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MASP1	NM_139125.4	c.1727G>T	p.Arg576Met	missense_variant	Exon 11 of 11	ENST00000296280.11	NP_624302.1
MASP1	NM_001879.6	c.1303+5337G>T		intron_variant	Intron 10 of 15	ENST00000337774.10	NP_001870.3
MASP1	NR_033519.2	n.1600G>T		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>T	p.Arg576Met	missense_variant	Exon 11 of 11	1	NM_139125.4	ENSP00000296280.7
MASP1	ENST00000337774.10	c.1303+5337G>T		intron_variant	Intron 10 of 15	1	NM_001879.6	ENSP00000336792.5

Frequencies

GnomAD3 genomes AF: 0.0674 AC: 10255 AN: 152154 Hom.: 608 Cov.: 33

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0415

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0978

Gnomad FIN AF: 0.0442

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0319

Gnomad OTH AF: 0.0603

GnomAD2 exomes AF: 0.0452 AC: 11312 AN: 250456 AF XY: 0.0456

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.0270

Gnomad ASJ exome AF: 0.0381

Gnomad EAS exome AF: 0.000871

Gnomad FIN exome AF: 0.0400

Gnomad NFE exome AF: 0.0324

Gnomad OTH exome AF: 0.0380

GnomAD4 exome AF: 0.0396 AC: 57871 AN: 1461668 Hom.: 1651 Cov.: 81 AF XY: 0.0404 AC XY: 29405 AN XY: 727162

African (AFR) AF: 0.156 AC: 5218 AN: 33480

American (AMR) AF: 0.0283 AC: 1267 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0371 AC: 970 AN: 26136

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39700

South Asian (SAS) AF: 0.0879 AC: 7578 AN: 86258

European-Finnish (FIN) AF: 0.0399 AC: 2122 AN: 53196

Middle Eastern (MID) AF: 0.0225 AC: 130 AN: 5768

European-Non Finnish (NFE) AF: 0.0342 AC: 38040 AN: 1112010

Other (OTH) AF: 0.0419 AC: 2530 AN: 60396

GnomAD4 genome AF: 0.0674 AC: 10264 AN: 152272 Hom.: 608 Cov.: 33 AF XY: 0.0673 AC XY: 5010 AN XY: 74442

African (AFR) AF: 0.150 AC: 6213 AN: 41530

American (AMR) AF: 0.0415 AC: 635 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 143 AN: 3468

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5184

South Asian (SAS) AF: 0.0975 AC: 471 AN: 4830

European-Finnish (FIN) AF: 0.0442 AC: 469 AN: 10606

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0319 AC: 2170 AN: 68032

Other (OTH) AF: 0.0597 AC: 126 AN: 2110

Alfa AF: 0.0415 Hom.: 716

Bravo AF: 0.0703

TwinsUK AF: 0.0410 AC: 152

ALSPAC AF: 0.0415 AC: 160

ESP6500AA AF: 0.139 AC: 611

ESP6500EA AF: 0.0333 AC: 286

ExAC AF: 0.0473 AC: 5742

Asia WGS AF: 0.0660 AC: 230 AN: 3478

EpiCase AF: 0.0308

EpiControl AF: 0.0309

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24023860) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

3MC syndrome 1 Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.4
DANN	Benign	0.87
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.52	T;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-0.96	T
PhyloP100		0.0040
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.089	T;T
Polyphen		0.011	B;B
Vest4		0.092
MPC		0.13
ClinPred		0.016	T
GERP RS		-0.34
gMVP		0.53
Mutation Taster		=93/7	polymorphism (auto)

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;