1-11037810-C-T

Variant names:

• chr1-11037810-C-T
• rs12142107
• NM_006610.4:c.891G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006610.4(MASP2):​c.891G>A​(p.Ala297Ala) 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.11
• Publications: 14 publications found

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]

MASP2 Gene-Disease associations (from GenCC):

• immunodeficiency due to MASP-2 deficiency

  Inheritance: AR Classification: STRONG Submitted by: Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -21 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 VariationId is 291790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
MASP2	NM_006610.4	c.891G>A	p.Ala297Ala	splice_region_variant, synonymous_variant	Exon 7 of 11	ENST00000400897.8	NP_006601.2
MASP2	XM_017000097.1	c.967G>A	p.Ala323Thr	missense_variant	Exon 7 of 7		XP_016855586.1
MASP2	XR_001736931.1	n.923G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MASP2	ENST00000400897.8	c.891G>A	p.Ala297Ala	splice_region_variant, synonymous_variant	Exon 7 of 11	1	NM_006610.4	ENSP00000383690.3

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

GnomAD2 exomes AF: 0.0584 AC: 14197 AN: 243076 AF XY: 0.0566

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 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

African (AFR) AF: 0.221 AC: 7296 AN: 32946

American (AMR) AF: 0.0743 AC: 3151 AN: 42434

Ashkenazi Jewish (ASJ) AF: 0.0488 AC: 1260 AN: 25810

East Asian (EAS) AF: 0.107 AC: 4195 AN: 39282

South Asian (SAS) AF: 0.106 AC: 8935 AN: 84292

European-Finnish (FIN) AF: 0.0157 AC: 838 AN: 53242

Middle Eastern (MID) AF: 0.0585 AC: 334 AN: 5710

European-Non Finnish (NFE) AF: 0.0205 AC: 22563 AN: 1102412

Other (OTH) AF: 0.0536 AC: 3198 AN: 59684

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

African (AFR) AF: 0.212 AC: 8787 AN: 41468

American (AMR) AF: 0.0709 AC: 1084 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0415 AC: 144 AN: 3468

East Asian (EAS) AF: 0.111 AC: 573 AN: 5180

South Asian (SAS) AF: 0.116 AC: 559 AN: 4820

European-Finnish (FIN) AF: 0.0151 AC: 160 AN: 10606

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0217 AC: 1478 AN: 68016

Other (OTH) AF: 0.0903 AC: 191 AN: 2114

Alfa AF: 0.0424 Hom.: 1331

Bravo AF: 0.0953

Asia WGS AF: 0.130 AC: 451 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency due to MASP-2 deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.062
DANN	Benign	0.90
PhyloP100		-1.1
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs12142107; hg19: chr1-11097867;