rs12142107

Positions:

• chr1-11037810-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_006610.4(MASP2):​c.891G>A​(p.Ala297=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0405 in 1,597,970 control chromosomes in the GnomAD database, including 3,350 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.086 (1139 hom., cov: 32)
  • Exomes 𝑓: 0.036 (2211 hom.)
• Consequence: MASP2 NM_006610.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0004358
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.11

Genes affected

MASP2 (HGNC:6902): (MBL associated serine protease 2) This gene encodes a member of the peptidase S1 family of serine proteases. The encoded preproprotein is proteolytically processed to generate A and B chains that heterodimerize to form the mature protease. This protease cleaves complement components C2 and C4 in order to generate C3 convertase in the lectin pathway of the complement system. The encoded protease also plays a role in the coagulation cascade through cleavage of prothrombin to form thrombin. Myocardial infarction and acute stroke patients exhibit reduced serum concentrations of the encoded protein. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-11037810-C-T is Benign according to our data. Variant chr1-11037810-C-T is described in ClinVar as [Benign]. Clinvar id is 291790.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MASP2	NM_006610.4	c.891G>A	p.Ala297=	splice_region_variant, synonymous_variant	7/11	ENST00000400897.8
MASP2	XM_017000097.1	c.967G>A	p.Ala323Thr	missense_variant	7/7
MASP2	XR_001736931.1	n.923G>A		splice_region_variant, non_coding_transcript_exon_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MASP2	ENST00000400897.8	c.891G>A	p.Ala297=	splice_region_variant, synonymous_variant	7/11	1	NM_006610.4	P1

Frequencies

GnomAD3 genomes AF: 0.0854 AC: 12989 AN: 152040 Hom.: 1136 Cov.: 32

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0707

Gnomad ASJ AF: 0.0415

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0151

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0908

GnomAD3 exomes AF: 0.0584 AC: 14197 AN: 243076 Hom.: 809 AF XY: 0.0566 AC XY: 7451 AN XY: 131558

Gnomad AFR exome AF: 0.213

Gnomad AMR exome AF: 0.0711

Gnomad ASJ exome AF: 0.0464

Gnomad EAS exome AF: 0.106

Gnomad SAS exome AF: 0.108

Gnomad FIN exome AF: 0.0163

Gnomad NFE exome AF: 0.0217

Gnomad OTH exome AF: 0.0492

GnomAD4 exome AF: 0.0358 AC: 51770 AN: 1445812 Hom.: 2211 Cov.: 27 AF XY: 0.0372 AC XY: 26757 AN XY: 719586

Gnomad4 AFR exome AF: 0.221

Gnomad4 AMR exome AF: 0.0743

Gnomad4 ASJ exome AF: 0.0488

Gnomad4 EAS exome AF: 0.107

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.0157

Gnomad4 NFE exome AF: 0.0205

Gnomad4 OTH exome AF: 0.0536

GnomAD4 genome AF: 0.0855 AC: 13013 AN: 152158 Hom.: 1139 Cov.: 32 AF XY: 0.0852 AC XY: 6339 AN XY: 74374

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.0709

Gnomad4 ASJ AF: 0.0415

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.116

Gnomad4 FIN AF: 0.0151

Gnomad4 NFE AF: 0.0217

Gnomad4 OTH AF: 0.0903

Alfa AF: 0.0378 Hom.: 480

Bravo AF: 0.0953

Asia WGS AF: 0.130 AC: 451 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency due to MASP-2 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.062
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00044
dbscSNV1_RF	Benign	0.010
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

Publications

LitVar

Other links and lift over

dbSNP: rs12142107; hg19: chr1-11097867;