rs12085877

Variant names:

• chr1-11027630-C-T
• rs12085877
• NM_006610.4:c.1316G>A

Variant summary

Our verdict is Benign. The variant received -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. 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.197
• Publications: 16 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]

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Genomics England PanelApp
• 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

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006610.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MASP2	NM_006610.4	MANE Select	c.1316G>A	p.Arg439His	missense	Exon 11 of 11	NP_006601.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MASP2	ENST00000400897.8	TSL:1 MANE Select	c.1316G>A	p.Arg439His	missense	Exon 11 of 11	ENSP00000383690.3	O00187-1
	MASP2	ENST00000860329.1		c.1376G>A	p.Arg459His	missense	Exon 12 of 12	ENSP00000530388.1
	MASP2	ENST00000700092.1		c.1295G>A	p.Arg432His	missense	Exon 11 of 11	ENSP00000514791.1	A0A8V8TQL2

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

GnomAD2 exomes AF: 0.00714 AC: 1745 AN: 244258 AF XY: 0.00515

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.: 34 AF XY: 0.00241 AC XY: 1748 AN XY: 724914

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: 1 AN: 25828

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.000175 AC: 15 AN: 85760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00383 AC: 22 AN: 5748

European-Non Finnish (NFE) AF: 0.000173 AC: 192 AN: 1109836

Other (OTH) AF: 0.00595 AC: 358 AN: 60208

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

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: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68030

Other (OTH) AF: 0.0170 AC: 36 AN: 2112

Alfa AF: 0.0105 Hom.: 187

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Immunodeficiency due to MASP-2 deficiency (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.20
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12085877; hg19: chr1-11087687;