chr15-74893329-A-G

Variant names:

• chr15-74893329-A-G
• rs7495739
• NM_002435.3:c.670+9A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002435.3(MPI):​c.670+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.509 in 1,613,370 control chromosomes in the GnomAD database, including 218,919 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16246 hom., cov: 33)
  • Exomes 𝑓: 0.52 (202673 hom.)
• Consequence: MPI NM_002435.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.68

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.217839E-5).
• BP6: Variant 15-74893329-A-G is Benign according to our data. Variant chr15-74893329-A-G is described in ClinVar as [Benign]. Clinvar id is 94069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-74893329-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPI	NM_002435.3	c.670+9A>G		intron_variant	Intron 5 of 7	ENST00000352410.9	NP_002426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPI	ENST00000352410.9	c.670+9A>G		intron_variant	Intron 5 of 7	1	NM_002435.3	ENSP00000318318.6

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68103 AN: 151966 Hom.: 16226 Cov.: 33

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.442

GnomAD3 exomes AF: 0.443 AC: 110737 AN: 249742 Hom.: 26725 AF XY: 0.433 AC XY: 58558 AN XY: 135140

Gnomad AFR exome AF: 0.332

Gnomad AMR exome AF: 0.520

Gnomad ASJ exome AF: 0.463

Gnomad EAS exome AF: 0.220

Gnomad SAS exome AF: 0.203

Gnomad FIN exome AF: 0.432

Gnomad NFE exome AF: 0.537

Gnomad OTH exome AF: 0.473

GnomAD4 exome AF: 0.515 AC: 752597 AN: 1461284 Hom.: 202673 Cov.: 40 AF XY: 0.505 AC XY: 366969 AN XY: 726964

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: 0.448 AC: 68177 AN: 152086 Hom.: 16246 Cov.: 33 AF XY: 0.438 AC XY: 32554 AN XY: 74362

Gnomad4 AFR AF: 0.339

Gnomad4 AMR AF: 0.514

Gnomad4 ASJ AF: 0.469

Gnomad4 EAS AF: 0.230

Gnomad4 SAS AF: 0.192

Gnomad4 FIN AF: 0.429

Gnomad4 NFE AF: 0.537

Gnomad4 OTH AF: 0.444

Alfa AF: 0.467 Hom.: 7641

Bravo AF: 0.458

TwinsUK AF: 0.578 AC: 2145

ALSPAC AF: 0.565 AC: 2178

ESP6500AA AF: 0.325 AC: 1428

ESP6500EA AF: 0.546 AC: 4690

ExAC AF: 0.436 AC: 52990

Asia WGS AF: 0.229 AC: 801 AN: 3478

EpiCase AF: 0.524

EpiControl AF: 0.523

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MPI-congenital disorder of glycosylation Benign:5

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	4.6
DANN	Benign	0.97
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.000062	T
PROVEAN	Benign	-1.1	N
Sift	Benign	0.51	T
Sift4G	Benign	0.43	T
Vest4		0.030
GERP RS		-0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs7495739; hg19: chr15-75185670; COSMIC: COSV60396694; COSMIC: COSV60396694;