rs72549154

Positions:

• chr3-187236144-C-A
• chr3-187236144-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/17 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
MASP1	NM_139125.4	c.1727G>T	p.Arg576Met	missense_variant	11/11	ENST00000296280.11	NP_624302.1
MASP1	NM_001879.6	c.1303+5337G>T		intron_variant		ENST00000337774.10	NP_001870.3
MASP1	NR_033519.2	n.1600G>T		non_coding_transcript_exon_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MASP1	ENST00000296280.11	c.1727G>T	p.Arg576Met	missense_variant	11/11	1	NM_139125.4	ENSP00000296280
MASP1	ENST00000337774.10	c.1303+5337G>T		intron_variant		1	NM_001879.6	ENSP00000336792	P1

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

GnomAD3 exomes AF: 0.0452 AC: 11312 AN: 250456 Hom.: 437 AF XY: 0.0456 AC XY: 6188 AN XY: 135688

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 SAS exome AF: 0.0924

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

Gnomad4 AFR exome AF: 0.156

Gnomad4 AMR exome AF: 0.0283

Gnomad4 ASJ exome AF: 0.0371

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.0879

Gnomad4 FIN exome AF: 0.0399

Gnomad4 NFE exome AF: 0.0342

Gnomad4 OTH exome AF: 0.0419

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

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.0415

Gnomad4 ASJ AF: 0.0412

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0975

Gnomad4 FIN AF: 0.0442

Gnomad4 NFE AF: 0.0319

Gnomad4 OTH AF: 0.0597

Alfa AF: 0.0376 Hom.: 271

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2018	This variant is associated with the following publications: (PMID: 24023860) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

3MC syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
MutationTaster	Benign	1.0	P;P;P
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

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

Other links and lift over

dbSNP: rs72549154; hg19: chr3-186953932;