rs2461280

Variant names:

• chr3-187236024-A-G
• rs2461280
• NM_139125.4:c.1847T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_139125.4(MASP1):​c.1847T>C​(p.Val616Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MASP1 NM_139125.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.32
• Publications: 1 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, Labcorp Genetics (formerly Invitae)
• 3MC syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33882946).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139125.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MASP1	NM_139125.4	MANE Select	c.1847T>C	p.Val616Ala	missense	Exon 11 of 11	NP_624302.1	P48740-2
	MASP1	NM_001879.6	MANE Plus Clinical	c.1303+5457T>C		intron	N/A	NP_001870.3
	MASP1	NR_033519.2		n.1720T>C		non_coding_transcript_exon	Exon 10 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MASP1	ENST00000296280.11	TSL:1 MANE Select	c.1847T>C	p.Val616Ala	missense	Exon 11 of 11	ENSP00000296280.7	P48740-2
	MASP1	ENST00000392472.6	TSL:1	c.1508T>C	p.Val503Ala	missense	Exon 10 of 10	ENSP00000376264.2	P48740-4
	MASP1	ENST00000337774.10	TSL:1 MANE Plus Clinical	c.1303+5457T>C		intron	N/A	ENSP00000336792.5	P48740-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 79

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.0029	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Benign	0.90
Eigen	Benign	-0.13
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.34	T
PhyloP100		5.3
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.84	N
REVEL	Uncertain	0.32
Sift	Benign	0.63	T
Sift4G	Benign	0.75	T
Polyphen		0.0010	B
Vest4		0.31
MutPred		0.53		Loss of stability (P = 0.028)
MVP		0.96
MPC		0.14
ClinPred		0.91	D
GERP RS		6.2
gMVP		0.41
Mutation Taster		=67/33	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: rs2461280; hg19: chr3-186953812;