rs28945068

Variant names:

• chr3-187241507-C-T
• rs28945068
• NM_139125.4:c.1277G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_139125.4(MASP1):​c.1277G>A​(p.Gly426Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,613,460 control chromosomes in the GnomAD database, including 234 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (13 hom., cov: 32)
  • Exomes 𝑓: 0.016 (221 hom.)
• Consequence: MASP1 NM_139125.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.07
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043150485).
• BP6: Variant 3-187241507-C-T is Benign according to our data. Variant chr3-187241507-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 463034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0121 (1836/152100) while in subpopulation NFE AF = 0.0178 (1208/67984). AF 95% confidence interval is 0.0169. There are 13 homozygotes in GnomAd4. There are 876 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.1277G>A	p.Gly426Glu	missense	Exon 10 of 11	NP_624302.1	P48740-2
	MASP1	NM_001879.6	MANE Plus Clinical	c.1277G>A	p.Gly426Glu	missense	Exon 10 of 16	NP_001870.3
	MASP1	NR_033519.2		n.1150G>A		non_coding_transcript_exon	Exon 9 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MASP1	ENST00000296280.11	TSL:1 MANE Select	c.1277G>A	p.Gly426Glu	missense	Exon 10 of 11	ENSP00000296280.7	P48740-2
	MASP1	ENST00000337774.10	TSL:1 MANE Plus Clinical	c.1277G>A	p.Gly426Glu	missense	Exon 10 of 16	ENSP00000336792.5	P48740-1
	MASP1	ENST00000392472.6	TSL:1	c.938G>A	p.Gly313Glu	missense	Exon 9 of 10	ENSP00000376264.2	P48740-4

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1836 AN: 151982 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0227

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0178

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.0122 AC: 3072 AN: 251482 AF XY: 0.0122

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00934

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0236

Gnomad NFE exome AF: 0.0180

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.0163 AC: 23840 AN: 1461360 Hom.: 221 Cov.: 30 AF XY: 0.0157 AC XY: 11429 AN XY: 726998

African (AFR) AF: 0.00218 AC: 73 AN: 33470

American (AMR) AF: 0.0103 AC: 462 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00179 AC: 154 AN: 86248

European-Finnish (FIN) AF: 0.0217 AC: 1160 AN: 53412

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5766

European-Non Finnish (NFE) AF: 0.0191 AC: 21185 AN: 1111526

Other (OTH) AF: 0.0125 AC: 752 AN: 60384

GnomAD4 genome AF: 0.0121 AC: 1836 AN: 152100 Hom.: 13 Cov.: 32 AF XY: 0.0118 AC XY: 876 AN XY: 74366

African (AFR) AF: 0.00301 AC: 125 AN: 41488

American (AMR) AF: 0.0136 AC: 208 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4814

European-Finnish (FIN) AF: 0.0227 AC: 241 AN: 10594

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

European-Non Finnish (NFE) AF: 0.0178 AC: 1208 AN: 67984

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

Alfa AF: 0.0142 Hom.: 44

Bravo AF: 0.0107

TwinsUK AF: 0.0213 AC: 79

ALSPAC AF: 0.0213 AC: 82

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0144 AC: 124

ExAC AF: 0.0118 AC: 1432

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	3MC syndrome 1 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.23
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.22
Sift	Benign	0.89	T
Sift4G	Benign	0.37	T
Polyphen		0.15	B
Vest4		0.20
MPC		0.18
ClinPred		0.037	T
GERP RS		3.1
Varity_R		0.37
gMVP		0.49
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs28945068; hg19: chr3-186959295; COSMIC: COSV51463870; COSMIC: COSV51463870;