rs73068950

Variant names:

• chr3-187236319-C-A
• rs73068950
• NM_139125.4:c.1552G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-187236319-C-A
• chr3-187236319-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_139125.4(MASP1):​c.1552G>T​(p.Val518Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. V518I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MASP1 NM_139125.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.37
• Publications: 2 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MASP1	NM_139125.4	MANE Select	c.1552G>T	p.Val518Phe	missense	Exon 11 of 11	NP_624302.1
	MASP1	NM_001879.6	MANE Plus Clinical	c.1303+5162G>T		intron	N/A	NP_001870.3
	MASP1	NR_033519.2		n.1425G>T		non_coding_transcript_exon	Exon 10 of 10

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MASP1	ENST00000296280.11	TSL:1 MANE Select	c.1552G>T	p.Val518Phe	missense	Exon 11 of 11	ENSP00000296280.7
	MASP1	ENST00000392472.6	TSL:1	c.1213G>T	p.Val405Phe	missense	Exon 10 of 10	ENSP00000376264.2
	MASP1	ENST00000337774.10	TSL:1 MANE Plus Clinical	c.1303+5162G>T		intron	N/A	ENSP00000336792.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 82

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		2.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.86
MutPred		0.64		Gain of glycosylation at Y519 (P = 0.0346)
MVP		0.93
MPC		0.64
ClinPred		0.96	D
GERP RS		5.1
gMVP		0.83
Mutation Taster		=46/54	disease causing

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: rs73068950; hg19: chr3-186954107;