rs116001173

Variant names:

• chr3-187253197-C-T
• rs116001173
• NM_139125.4:c.863G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-187253197-C-T
• chr3-187253197-C-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_139125.4(MASP1):​c.863G>A​(p.Arg288Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,614,108 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R288W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: MASP1 NM_139125.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.89
• 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, Labcorp Genetics (formerly Invitae)
• 3MC syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014130175).
• BP6: Variant 3-187253197-C-T is Benign according to our data. Variant chr3-187253197-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285534.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00108 (164/152262) while in subpopulation AFR AF = 0.00352 (146/41534). AF 95% confidence interval is 0.00305. There are 1 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.863G>A	p.Arg288Gln	missense	Exon 6 of 11	NP_624302.1	P48740-2
	MASP1	NM_001879.6	MANE Plus Clinical	c.863G>A	p.Arg288Gln	missense	Exon 6 of 16	NP_001870.3
	MASP1	NM_001031849.3		c.863G>A	p.Arg288Gln	missense	Exon 6 of 9	NP_001027019.1	P48740-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MASP1	ENST00000296280.11	TSL:1 MANE Select	c.863G>A	p.Arg288Gln	missense	Exon 6 of 11	ENSP00000296280.7	P48740-2
	MASP1	ENST00000337774.10	TSL:1 MANE Plus Clinical	c.863G>A	p.Arg288Gln	missense	Exon 6 of 16	ENSP00000336792.5	P48740-1
	MASP1	ENST00000392472.6	TSL:1	c.524G>A	p.Arg175Gln	missense	Exon 5 of 10	ENSP00000376264.2	P48740-4

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152144 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00348

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000278 AC: 70 AN: 251426 AF XY: 0.000155

Gnomad AFR exome AF: 0.00326

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000180 AC: 263 AN: 1461846 Hom.: 2 Cov.: 32 AF XY: 0.000158 AC XY: 115 AN XY: 727224

African (AFR) AF: 0.00460 AC: 154 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5750

European-Non Finnish (NFE) AF: 0.0000468 AC: 52 AN: 1111992

Other (OTH) AF: 0.000265 AC: 16 AN: 60396

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152262 Hom.: 1 Cov.: 32 AF XY: 0.000954 AC XY: 71 AN XY: 74436

African (AFR) AF: 0.00352 AC: 146 AN: 41534

American (AMR) AF: 0.000915 AC: 14 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00139 Hom.: 1

Bravo AF: 0.00130

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000412 AC: 50

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	3MC syndrome 1 (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	MASP1-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.70	N
PhyloP100		1.9
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.021
Sift	Benign	0.45	T
Sift4G	Benign	0.57	T
Polyphen		0.026	B
Vest4		0.087
MVP		0.22
MPC		0.14
ClinPred		0.0097	T
GERP RS		2.0
Varity_R		0.14
gMVP		0.36
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs116001173; hg19: chr3-186970985; COSMIC: COSV51460220; COSMIC: COSV51460220;