rs12440159

Positions:

• chr15-74896243-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.762C>T​(p.Ile254=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00659 in 1,614,204 control chromosomes in the GnomAD database, including 501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (42 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (459 hom.)
• Consequence: MPI NM_002435.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.09

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=-0.35).
• BP6: Variant 15-74896243-C-T is Benign according to our data. Variant chr15-74896243-C-T is described in ClinVar as [Benign]. Clinvar id is 94071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPI	NM_002435.3	c.762C>T	p.Ile254=	synonymous_variant	6/8	ENST00000352410.9	NP_002426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPI	ENST00000352410.9	c.762C>T	p.Ile254=	synonymous_variant	6/8	1	NM_002435.3	ENSP00000318318	P1

Frequencies

GnomAD3 genomes AF: 0.00954 AC: 1452 AN: 152192 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.00642

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0545

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0491

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.0214 AC: 5381 AN: 251480 Hom.: 303 AF XY: 0.0177 AC XY: 2405 AN XY: 135914

Gnomad AFR exome AF: 0.00658

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0404

Gnomad SAS exome AF: 0.00905

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.00628 AC: 9175 AN: 1461894 Hom.: 459 Cov.: 31 AF XY: 0.00595 AC XY: 4328 AN XY: 727248

Gnomad4 AFR exome AF: 0.00538

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.00367

Gnomad4 EAS exome AF: 0.0664

Gnomad4 SAS exome AF: 0.00836

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.00631

GnomAD4 genome AF: 0.00960 AC: 1462 AN: 152310 Hom.: 42 Cov.: 32 AF XY: 0.0101 AC XY: 754 AN XY: 74488

Gnomad4 AFR AF: 0.00642

Gnomad4 AMR AF: 0.0545

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.0494

Gnomad4 SAS AF: 0.0122

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00498 Hom.: 40

Bravo AF: 0.0150

Asia WGS AF: 0.0420 AC: 146 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 14, 2014	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	11
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12440159; hg19: chr15-75188584; COSMIC: COSV60397121; COSMIC: COSV60397121;