rs12085877

Positions:

• chr1-11027630-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006610.4(MASP2):​c.1316G>A​(p.Arg439His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,610,136 control chromosomes in the GnomAD database, including 375 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R439C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.027 (187 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (188 hom.)
• Consequence: MASP2 NM_006610.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.197

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]

TARDBP (HGNC:11571): (TAR DNA binding protein) HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNA genome that produces a chromosomally integrated DNA during the replicative cycle. Activation of HIV-1 gene expression by the transactivator Tat is dependent on an RNA regulatory element (TAR) located downstream of the transcription initiation site. The protein encoded by this gene is a transcriptional repressor that binds to chromosomally integrated TAR DNA and represses HIV-1 transcription. In addition, this protein regulates alternate splicing of the CFTR gene. A similar pseudogene is present on chromosome 20. [provided by RefSeq, Jul 2008]

MASP2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022631288).
• BP6: Variant 1-11027630-C-T is Benign according to our data. Variant chr1-11027630-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 291782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0923 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MASP2	NM_006610.4	c.1316G>A	p.Arg439His	missense_variant	11/11	ENST00000400897.8	NP_006601.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MASP2	ENST00000400897.8	c.1316G>A	p.Arg439His	missense_variant	11/11	1	NM_006610.4	ENSP00000383690.3

Frequencies

GnomAD3 genomes AF: 0.0271 AC: 4126 AN: 152130 Hom.: 187 Cov.: 33

Gnomad AFR AF: 0.0950

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00865

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.00714 AC: 1745 AN: 244258 Hom.: 74 AF XY: 0.00515 AC XY: 683 AN XY: 132568

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.00369

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000134

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000329

Gnomad OTH exome AF: 0.00301

GnomAD4 exome AF: 0.00288 AC: 4195 AN: 1457888 Hom.: 188 Cov.: 34 AF XY: 0.00241 AC XY: 1748 AN XY: 724914

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.00421

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000175

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000173

Gnomad4 OTH exome AF: 0.00595

GnomAD4 genome AF: 0.0271 AC: 4127 AN: 152248 Hom.: 187 Cov.: 33 AF XY: 0.0260 AC XY: 1932 AN XY: 74426

Gnomad4 AFR AF: 0.0948

Gnomad4 AMR AF: 0.00864

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00532 Hom.: 77

Bravo AF: 0.0313

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0939 AC: 413

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00872 AC: 1059

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2018	- -

Immunodeficiency due to MASP-2 deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.087	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.67	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.23
Sift	Benign	0.13	T
Sift4G	Benign	0.25	T
Polyphen		0.0040	B
Vest4		0.14
MVP		0.75
MPC		0.044
ClinPred		0.0090	T
GERP RS		-0.49
Varity_R		0.13
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs12085877; hg19: chr1-11087687;