rs1782455

chr1-11027467-G-Achr1-11027467-G-Cchr1-11027467-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006610.4(MASP2):c.1479C>T(p.Ser493=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.806 in 1,613,586 control chromosomes in the GnomAD database, including 534,265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (39519 hom., cov: 31)
  • Exomes 𝑓: 0.82 (494746 hom.)
• Consequence: MASP2 NM_006610.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.31

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-11027467-G-A is Benign according to our data. Variant chr1-11027467-G-A is described in ClinVar as [Benign]. Clinvar id is 291781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11027467-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.842 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MASP2	NM_006610.4	c.1479C>T	p.Ser493=	synonymous_variant	11/11	ENST00000400897.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MASP2	ENST00000400897.8	c.1479C>T	p.Ser493=	synonymous_variant	11/11	1	NM_006610.4	P1

Frequencies

GnomAD3 genomes AF: 0.689 AC: 104692 AN: 151866 Hom.: 39509 Cov.: 31

Gnomad AFR AF: 0.352

Gnomad AMI AF: 0.890

Gnomad AMR AF: 0.758

Gnomad ASJ AF: 0.725

Gnomad EAS AF: 0.864

Gnomad SAS AF: 0.793

Gnomad FIN AF: 0.827

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.831

Gnomad OTH AF: 0.737

GnomAD3 exomes AF: 0.793 AC: 199509 AN: 251474 Hom.: 81163 AF XY: 0.800 AC XY: 108673 AN XY: 135910

Gnomad AFR exome AF: 0.339

Gnomad AMR exome AF: 0.825

Gnomad ASJ exome AF: 0.732

Gnomad EAS exome AF: 0.867

Gnomad SAS exome AF: 0.793

Gnomad FIN exome AF: 0.830

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.799

GnomAD4 exome AF: 0.818 AC: 1196308 AN: 1461602 Hom.: 494746 Cov.: 52 AF XY: 0.818 AC XY: 595118 AN XY: 727126

Gnomad4 AFR exome AF: 0.321

Gnomad4 AMR exome AF: 0.818

Gnomad4 ASJ exome AF: 0.733

Gnomad4 EAS exome AF: 0.870

Gnomad4 SAS exome AF: 0.790

Gnomad4 FIN exome AF: 0.832

Gnomad4 NFE exome AF: 0.837

Gnomad4 OTH exome AF: 0.795

GnomAD4 genome AF: 0.689 AC: 104739 AN: 151984 Hom.: 39519 Cov.: 31 AF XY: 0.692 AC XY: 51388 AN XY: 74284

Gnomad4 AFR AF: 0.352

Gnomad4 AMR AF: 0.759

Gnomad4 ASJ AF: 0.725

Gnomad4 EAS AF: 0.864

Gnomad4 SAS AF: 0.793

Gnomad4 FIN AF: 0.827

Gnomad4 NFE AF: 0.831

Gnomad4 OTH AF: 0.740

Alfa AF: 0.785 Hom.: 58219

Bravo AF: 0.671

Asia WGS AF: 0.782 AC: 2718 AN: 3478

EpiCase AF: 0.825

EpiControl AF: 0.828

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Immunodeficiency due to MASP-2 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Amyotrophic Lateral Sclerosis, Dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Frontotemporal dementia Benign:1

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
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.7
Dann	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1782455; hg19: chr1-11087524; COSMIC: COSV53571447; COSMIC: COSV53571447;