Genetic Variant NM_139125.4:c.1386G>A (chr3-187236485-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_139125.4(MASP1):c.1386G>A(p.Pro462Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,614,034 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 35 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 52 hom. )

Consequence

MASP1
NM_139125.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.31

Publications

1 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 3-187236485-C-T is Benign according to our data. Variant chr3-187236485-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 463035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.32 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0124 (1888/152270) while in subpopulation AFR AF = 0.0437 (1814/41534). AF 95% confidence interval is 0.042. There are 35 homozygotes in GnomAd4. There are 877 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 35 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.1386G>A	p.Pro462Pro	synonymous	Exon 11 of 11	NP_624302.1
MASP1	NM_001879.6	MANE Plus Clinical	c.1303+4996G>A		intron	N/A	NP_001870.3
MASP1	NR_033519.2		n.1259G>A		non_coding_transcript_exon	Exon 10 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MASP1	ENST00000296280.11	TSL:1 MANE Select	c.1386G>A	p.Pro462Pro	synonymous	Exon 11 of 11	ENSP00000296280.7
MASP1	ENST00000392472.6	TSL:1	c.1047G>A	p.Pro349Pro	synonymous	Exon 10 of 10	ENSP00000376264.2
MASP1	ENST00000337774.10	TSL:1 MANE Plus Clinical	c.1303+4996G>A		intron	N/A	ENSP00000336792.5

Frequencies

GnomAD3 genomes

AF:

0.0124

AC:

1888

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0438

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00326

AC:

820

AN:

251344

AF XY:

0.00242

show subpopulations

Gnomad AFR exome

AF:

0.0448

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.000994

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.00134

AC:

1955

AN:

1461764

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

837

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.0463

AC:

1550

AN:

33480

American (AMR)

AF:

0.00224

AC:

100

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00119

AC:

AN:

26134

East Asian (EAS)

AF:

0.00118

AC:

AN:

39698

South Asian (SAS)

AF:

0.000162

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000396

AC:

AN:

1111984

Other (OTH)

AF:

0.00262

AC:

158

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

122

244

367

489

611

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.0124

AC:

1888

AN:

152270

Hom.:

Cov.:

AF XY:

0.0118

AC XY:

877

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0437

AC:

1814

AN:

41534

American (AMR)

AF:

0.00314

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.000580

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68034

Other (OTH)

AF:

0.00663

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

176

263

351

439

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00549

Hom.:

Bravo

AF:

0.0141

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

3MC syndrome 1

Benign:2

Oct 18, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Nov 27, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.020

(source)

DANN

Benign

0.54

PhyloP100

-2.3

Mutation Taster

=98/2

polymorphism

(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

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