rs1130741

chr15-74897589-A-Gchr15-74897589-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002435.3(MPI):c.1131A>G(p.Val377=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.509 in 1,613,846 control chromosomes in the GnomAD database, including 219,264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16292 hom., cov: 32)
  • Exomes 𝑓: 0.52 (202972 hom.)
• Consequence: MPI NM_002435.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.478

Genes affected

MPI (HGNC:7216): (mannose phosphate isomerase) Phosphomannose isomerase catalyzes the interconversion of fructose-6-phosphate and mannose-6-phosphate and plays a critical role in maintaining the supply of D-mannose derivatives, which are required for most glycosylation reactions. Mutations in the MPI gene were found in patients with carbohydrate-deficient glycoprotein syndrome, type Ib. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 15-74897589-A-G is Benign according to our data. Variant chr15-74897589-A-G is described in ClinVar as [Benign]. Clinvar id is 94066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-74897589-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.478 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPI	NM_002435.3	c.1131A>G	p.Val377=	synonymous_variant	8/8	ENST00000352410.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPI	ENST00000352410.9	c.1131A>G	p.Val377=	synonymous_variant	8/8	1	NM_002435.3	P1

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68180 AN: 151932 Hom.: 16271 Cov.: 32

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.515

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.442

GnomAD3 exomes AF: 0.445 AC: 111822 AN: 251392 Hom.: 27095 AF XY: 0.435 AC XY: 59083 AN XY: 135872

Gnomad AFR exome AF: 0.332

Gnomad AMR exome AF: 0.520

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.220

Gnomad SAS exome AF: 0.204

Gnomad FIN exome AF: 0.432

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.473

GnomAD4 exome AF: 0.515 AC: 753438 AN: 1461796 Hom.: 202972 Cov.: 55 AF XY: 0.505 AC XY: 367431 AN XY: 727218

Gnomad4 AFR exome AF: 0.331

Gnomad4 AMR exome AF: 0.523

Gnomad4 ASJ exome AF: 0.468

Gnomad4 EAS exome AF: 0.245

Gnomad4 SAS exome AF: 0.208

Gnomad4 FIN exome AF: 0.438

Gnomad4 NFE exome AF: 0.561

Gnomad4 OTH exome AF: 0.483

GnomAD4 genome AF: 0.449 AC: 68256 AN: 152050 Hom.: 16292 Cov.: 32 AF XY: 0.439 AC XY: 32586 AN XY: 74308

Gnomad4 AFR AF: 0.339

Gnomad4 AMR AF: 0.515

Gnomad4 ASJ AF: 0.469

Gnomad4 EAS AF: 0.230

Gnomad4 SAS AF: 0.192

Gnomad4 FIN AF: 0.430

Gnomad4 NFE AF: 0.538

Gnomad4 OTH AF: 0.443

Alfa AF: 0.512 Hom.: 42943

Bravo AF: 0.458

Asia WGS AF: 0.229 AC: 800 AN: 3478

EpiCase AF: 0.524

EpiControl AF: 0.524

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 44% of total chromosomes in ExAC -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

MPI-congenital disorder of glycosylation Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	7.4
Dann	Benign	0.68

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

LitVar

Other links and lift over

dbSNP: rs1130741; hg19: chr15-75189930; COSMIC: COSV60396702; COSMIC: COSV60396702;