rs1553786749

Variant names:

• chr3-187286003-T-C
• rs1553786749
• NM_139125.4:c.59A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_139125.4(MASP1):​c.59A>G​(p.His20Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MASP1 NM_139125.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.67

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16602072).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MASP1	NM_139125.4	c.59A>G	p.His20Arg	missense_variant	Exon 2 of 11	ENST00000296280.11	NP_624302.1
MASP1	NM_001879.6	c.59A>G	p.His20Arg	missense_variant	Exon 2 of 16	ENST00000337774.10	NP_001870.3
MASP1	NM_001031849.3	c.59A>G	p.His20Arg	missense_variant	Exon 2 of 9		NP_001027019.1
MASP1	NR_033519.2	n.110+5625A>G		intron_variant	Intron 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MASP1	ENST00000296280.11	c.59A>G	p.His20Arg	missense_variant	Exon 2 of 11	1	NM_139125.4	ENSP00000296280.7
MASP1	ENST00000337774.10	c.59A>G	p.His20Arg	missense_variant	Exon 2 of 16	1	NM_001879.6	ENSP00000336792.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 03, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Benign	0.83
DEOGEN2	Benign	0.073	T;.;.;.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.78	T;T;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.69	N;N;N;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.42	T;T;T;T;T
Sift4G	Benign	0.11	T;T;T;.;.
Polyphen		0.13	B;B;B;.;.
Vest4		0.46
MutPred		0.60		Gain of ubiquitination at K16 (P = 0.0688);Gain of ubiquitination at K16 (P = 0.0688);Gain of ubiquitination at K16 (P = 0.0688);.;.;
MVP		0.72
MPC		0.15
ClinPred		0.18	T
GERP RS		4.1
Varity_R		0.094
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553786749; hg19: chr3-187003791;