rs35384947

Positions:

• chr3-187236485-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.31

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MASP1	NM_139125.4	c.1386G>A	p.Pro462Pro	synonymous_variant	11/11	ENST00000296280.11	NP_624302.1
MASP1	NM_001879.6	c.1303+4996G>A		intron_variant		ENST00000337774.10	NP_001870.3
MASP1	NR_033519.2	n.1259G>A		non_coding_transcript_exon_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MASP1	ENST00000296280.11	c.1386G>A	p.Pro462Pro	synonymous_variant	11/11	1	NM_139125.4	ENSP00000296280.7
MASP1	ENST00000337774.10	c.1303+4996G>A		intron_variant		1	NM_001879.6	ENSP00000336792.5

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1888 AN: 152152 Hom.: 35 Cov.: 33

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

GnomAD3 exomes AF: 0.00326 AC: 820 AN: 251344 Hom.: 18 AF XY: 0.00242 AC XY: 329 AN XY: 135834

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 SAS exome AF: 0.000131

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.: 52 Cov.: 82 AF XY: 0.00115 AC XY: 837 AN XY: 727196

Gnomad4 AFR exome AF: 0.0463

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00118

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.00262

GnomAD4 genome AF: 0.0124 AC: 1888 AN: 152270 Hom.: 35 Cov.: 33 AF XY: 0.0118 AC XY: 877 AN XY: 74456

Gnomad4 AFR AF: 0.0437

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00514 Hom.: 10

Bravo AF: 0.0141

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3MC syndrome 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.020
DANN	Benign	0.54

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

LitVar

Other links and lift over

dbSNP: rs35384947; hg19: chr3-186954273; COSMIC: COSV56220834;