rs533236263

Variant names:

• chr3-187235812-C-A
• rs533236263
• NM_139125.4:c.2059G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-187235812-C-A
• chr3-187235812-C-G
• chr3-187235812-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_139125.4(MASP1):​c.2059G>T​(p.Gly687Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G687R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MASP1 NM_139125.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• 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_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-187235812-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30077.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

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.2059G>T	p.Gly687Trp	missense	Exon 11 of 11	NP_624302.1
	MASP1	NM_001879.6	MANE Plus Clinical	c.1303+5669G>T		intron	N/A	NP_001870.3
	MASP1	NR_033519.2		n.1932G>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.2059G>T	p.Gly687Trp	missense	Exon 11 of 11	ENSP00000296280.7
	MASP1	ENST00000392472.6	TSL:1	c.1720G>T	p.Gly574Trp	missense	Exon 10 of 10	ENSP00000376264.2
	MASP1	ENST00000337774.10	TSL:1 MANE Plus Clinical	c.1303+5669G>T		intron	N/A	ENSP00000336792.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 67 AF XY: 0.00 AC XY: 0 AN XY: 727244

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: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.95		Loss of disorder (P = 0.0055)
MVP		0.97
MPC		0.61
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.88
Mutation Taster		=7/93	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: rs533236263; hg19: chr3-186953600;