3-187236319-C-T

Variant names:

• chr3-187236319-C-T
• rs73068950
• NM_139125.4:c.1552G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_139125.4(MASP1):​c.1552G>A​(p.Val518Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000642 in 1,614,254 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (4 hom.)
• Consequence: MASP1 NM_139125.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.37
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009975851).
• BP6: Variant 3-187236319-C-T is Benign according to our data. Variant chr3-187236319-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 702180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00307 (468/152362) while in subpopulation AFR AF = 0.0103 (428/41586). AF 95% confidence interval is 0.00949. There are 0 homozygotes in GnomAd4. There are 207 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MASP1	NM_139125.4	MANE Select	c.1552G>A	p.Val518Ile	missense	Exon 11 of 11	NP_624302.1
	MASP1	NM_001879.6	MANE Plus Clinical	c.1303+5162G>A		intron	N/A	NP_001870.3
	MASP1	NR_033519.2		n.1425G>A		non_coding_transcript_exon	Exon 10 of 10

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MASP1	ENST00000296280.11	TSL:1 MANE Select	c.1552G>A	p.Val518Ile	missense	Exon 11 of 11	ENSP00000296280.7
	MASP1	ENST00000392472.6	TSL:1	c.1213G>A	p.Val405Ile	missense	Exon 10 of 10	ENSP00000376264.2
	MASP1	ENST00000337774.10	TSL:1 MANE Plus Clinical	c.1303+5162G>A		intron	N/A	ENSP00000336792.5

Frequencies

GnomAD3 genomes AF: 0.00308 AC: 469 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000875 AC: 220 AN: 251292 AF XY: 0.000670

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000389 AC: 569 AN: 1461892 Hom.: 4 Cov.: 82 AF XY: 0.000378 AC XY: 275 AN XY: 727246

African (AFR) AF: 0.0103 AC: 345 AN: 33480

American (AMR) AF: 0.000671 AC: 30 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000614 AC: 53 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000845 AC: 94 AN: 1112012

Other (OTH) AF: 0.000778 AC: 47 AN: 60396

GnomAD4 genome AF: 0.00307 AC: 468 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.00278 AC XY: 207 AN XY: 74512

African (AFR) AF: 0.0103 AC: 428 AN: 41586

American (AMR) AF: 0.00202 AC: 31 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00118 Hom.: 1

Bravo AF: 0.00370

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00118 AC: 143

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	3MC syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Benign	0.90
Eigen	Benign	-0.14
Eigen_PC	Benign	0.017
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.18	D
PhyloP100		2.4
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.030	N
REVEL	Uncertain	0.35
Sift	Benign	0.83	T
Sift4G	Benign	0.61	T
Polyphen		0.046	B
Vest4		0.20
MVP		0.64
MPC		0.14
ClinPred		0.026	T
GERP RS		5.1
gMVP		0.27
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs73068950; hg19: chr3-186954107; COSMIC: COSV99962716;