rs139190144

Positions:

• chr15-74896165-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002435.3(MPI):​c.684C>T​(p.Asn228=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0281 in 1,614,080 control chromosomes in the GnomAD database, including 886 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (60 hom., cov: 32)
  • Exomes 𝑓: 0.029 (826 hom.)
• Consequence: MPI NM_002435.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.96

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 15-74896165-C-T is Benign according to our data. Variant chr15-74896165-C-T is described in ClinVar as [Benign]. Clinvar id is 167305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-74896165-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.96 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPI	NM_002435.3	c.684C>T	p.Asn228=	synonymous_variant	6/8	ENST00000352410.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPI	ENST00000352410.9	c.684C>T	p.Asn228=	synonymous_variant	6/8	1	NM_002435.3	P1

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 3240 AN: 152140 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.00490

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0689

Gnomad FIN AF: 0.0395

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0281

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.0254 AC: 6388 AN: 251398 Hom.: 155 AF XY: 0.0287 AC XY: 3899 AN XY: 135872

Gnomad AFR exome AF: 0.00492

Gnomad AMR exome AF: 0.00809

Gnomad ASJ exome AF: 0.00804

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0656

Gnomad FIN exome AF: 0.0352

Gnomad NFE exome AF: 0.0268

Gnomad OTH exome AF: 0.0213

GnomAD4 exome AF: 0.0288 AC: 42143 AN: 1461822 Hom.: 826 Cov.: 31 AF XY: 0.0301 AC XY: 21902 AN XY: 727204

Gnomad4 AFR exome AF: 0.00424

Gnomad4 AMR exome AF: 0.00941

Gnomad4 ASJ exome AF: 0.00650

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0665

Gnomad4 FIN exome AF: 0.0356

Gnomad4 NFE exome AF: 0.0289

Gnomad4 OTH exome AF: 0.0241

GnomAD4 genome AF: 0.0213 AC: 3242 AN: 152258 Hom.: 60 Cov.: 32 AF XY: 0.0225 AC XY: 1677 AN XY: 74438

Gnomad4 AFR AF: 0.00488

Gnomad4 AMR AF: 0.0141

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0696

Gnomad4 FIN AF: 0.0395

Gnomad4 NFE AF: 0.0281

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0220 Hom.: 28

Bravo AF: 0.0175

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.0293

EpiControl AF: 0.0260

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2016	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. -

MPI-congenital disorder of glycosylation Benign:3

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, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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	-0.45
CADD	Benign	15
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs139190144; hg19: chr15-75188506;