chr1-11027630-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 16/21 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.197

Publications

16 publications found

Variant links:

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 links:

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]

TARDBP Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis type 10
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
frontotemporal dementia with motor neuron disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
inclusion body myositis
Inheritance: AD Classification: LIMITED Submitted by: Broad Center for Mendelian Genomics

TARDBP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
MASP2	NM_006610.4 link	c.1316G>A	p.Arg439His	missense_variant	Exon 11 of 11	ENST00000400897.8	NP_006601.2	O00187-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MASP2	ENST00000400897.8 link	c.1316G>A	p.Arg439His	missense_variant	Exon 11 of 11	1	NM_006610.4	ENSP00000383690.3		O00187-1

Frequencies

GnomAD3 genomes

AF:

0.0271

AC:

4126

AN:

152130

Hom.:

187

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00714

AC:

1745

AN:

244258

AF XY:

0.00515

show subpopulations

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 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.:

AF XY:

0.00241

AC XY:

1748

AN XY:

724914

show subpopulations

African (AFR)

AF:

0.103

AC:

3421

AN:

33322

American (AMR)

AF:

0.00421

AC:

186

AN:

44224

Ashkenazi Jewish (ASJ)

AF:

0.0000387

AC:

AN:

25828

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.000175

AC:

AN:

85760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53304

Middle Eastern (MID)

AF:

0.00383

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.000173

AC:

192

AN:

1109836

Other (OTH)

AF:

0.00595

AC:

358

AN:

60208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

187

374

562

749

936

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

216

324

432

540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0271

AC:

4127

AN:

152248

Hom.:

187

Cov.:

AF XY:

0.0260

AC XY:

1932

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0948

AC:

3935

AN:

41520

American (AMR)

AF:

0.00864

AC:

132

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68030

Other (OTH)

AF:

0.0170

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

181

362

542

723

904

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0105

Hom.:

187

Bravo

AF:

0.0313

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0939

AC:

413

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00872

AC:

1059

Asia WGS

AF:

0.00751

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Immunodeficiency due to MASP-2 deficiency

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.087

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0023

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.67

PhyloP100

-0.20

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.1

REVEL

Benign

0.23

Sift

Benign

0.13

Sift4G

Benign

0.25

Polyphen

0.0040

Vest4

0.14

MVP

0.75

MPC

0.044

ClinPred

0.0090

GERP RS

-0.49

Varity_R

0.13

gMVP

0.32

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over