Genetic Variant MASP1:p.Thr354Thr (chr3-187250279-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_139125.4(MASP1):c.1062G>A(p.Thr354Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,613,946 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 19 hom. )

Consequence

MASP1
NM_139125.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -5.87

Publications

2 publications found

Variant links:

Genes affected

MASP1 (HGNC:6901): (MBL associated serine protease 1) This gene encodes a serine protease that functions as a component of the lectin pathway of complement activation. The complement pathway plays an essential role in the innate and adaptive immune response. The encoded protein is synthesized as a zymogen and is activated when it complexes with the pathogen recognition molecules of lectin pathway, the mannose-binding lectin and the ficolins. This protein is not directly involved in complement activation but may play a role as an amplifier of complement activation by cleaving complement C2 or by activating another complement serine protease, MASP-2. The encoded protein is also able to cleave fibrinogen and factor XIII and may may be involved in coagulation. A splice variant of this gene which lacks the serine protease domain functions as an inhibitor of the complement pathway. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

MASP1 Gene-Disease associations (from GenCC):

3MC syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
3MC syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MASP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 3-187250279-C-T is Benign according to our data. Variant chr3-187250279-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 531897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.87 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00401 (611/152312) while in subpopulation AFR AF = 0.00868 (361/41572). AF 95% confidence interval is 0.00795. There are 4 homozygotes in GnomAd4. There are 336 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139125.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MASP1	NM_139125.4	MANE Select	c.1062G>A	p.Thr354Thr	synonymous	Exon 8 of 11	NP_624302.1
MASP1	NM_001879.6	MANE Plus Clinical	c.1062G>A	p.Thr354Thr	synonymous	Exon 8 of 16	NP_001870.3
MASP1	NM_001031849.3		c.1062G>A	p.Thr354Thr	synonymous	Exon 8 of 9	NP_001027019.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MASP1	ENST00000296280.11	TSL:1 MANE Select	c.1062G>A	p.Thr354Thr	synonymous	Exon 8 of 11	ENSP00000296280.7
MASP1	ENST00000337774.10	TSL:1 MANE Plus Clinical	c.1062G>A	p.Thr354Thr	synonymous	Exon 8 of 16	ENSP00000336792.5
MASP1	ENST00000392472.6	TSL:1	c.723G>A	p.Thr241Thr	synonymous	Exon 7 of 10	ENSP00000376264.2

Frequencies

GnomAD3 genomes

AF:

0.00394

AC:

599

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00842

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0182

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00242

AC:

609

AN:

251458

AF XY:

0.00213

show subpopulations

Gnomad AFR exome

AF:

0.00886

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0179

Gnomad NFE exome

AF:

0.000334

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00111

AC:

1620

AN:

1461634

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

761

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.00953

AC:

319

AN:

33476

American (AMR)

AF:

0.000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.000278

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0185

AC:

990

AN:

53418

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000172

AC:

191

AN:

1111776

Other (OTH)

AF:

0.00118

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

193

289

386

482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00401

AC:

611

AN:

152312

Hom.:

Cov.:

AF XY:

0.00451

AC XY:

336

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00868

AC:

361

AN:

41572

American (AMR)

AF:

0.000785

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0182

AC:

193

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68024

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00165

Hom.:

Bravo

AF:

0.00316

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

3MC syndrome 1

Benign:1

Sep 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MASP1: BP4, BP7, BS2

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

1.6

(source)

DANN

Benign

0.62

PhyloP100

-5.9

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over