rs104894489

chr15-74893306-G-Achr15-74893306-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_002435.3(MPI):c.656G>A(p.Arg219Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R219R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: MPI NM_002435.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.62

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-74893306-G-A is Pathogenic according to our data. Variant chr15-74893306-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-74893306-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPI	NM_002435.3	c.656G>A	p.Arg219Gln	missense_variant	5/8	ENST00000352410.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPI	ENST00000352410.9	c.656G>A	p.Arg219Gln	missense_variant	5/8	1	NM_002435.3	P1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000291 AC: 73 AN: 250746 Hom.: 0 AF XY: 0.000295 AC XY: 40 AN XY: 135612

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000540

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000276 AC: 403 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.000270 AC XY: 196 AN XY: 727240

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.000314

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74364

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000194 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000453 AC: 55

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MPI-congenital disorder of glycosylation Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 219 of the MPI protein (p.Arg219Gln). This variant is present in population databases (rs104894489, gnomAD 0.05%). This missense change has been observed in individual(s) with CDG type Ib (PMID: 10980531, 11350186, 18928705). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14345). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MPI protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MPI function (PMID: 9525984, 24421398). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jul 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 18, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The MPI c.656G>A (p.Arg219Gln) missense variant has been reported in five studies in which it is found in a total of six individuals with MPI- congenital disorders of glycosylation (CDG-Ib), including one homozygote and five compound heterozygotes (Niehues et al. 1998; Schollen et al. 2000; Westphal et al. 2001; Martín Hernández et al. 2008; Helander et al. 2014). The variant was also identified in a homozygous state in an individual who showed elevated carbohydrate-deficient transferrin levels but no other clinical signs of MPI-CDG (CDG-Ib), and in a heterozygous state in three unaffected parents of patients. The variant was absent from 50 controls but is reported at a frequency of 0.00078 in the European (non-Finnish) population of the Exome Aggregation Consortium. Expression studies in COS-7 cells showed that the variant protein resulted in MPI activity indistinguishable from background, while expression of normal MPI increased specific activity approximately 10 fold when compared with controls (Niehues et al. 1998). Based on the collective evidence, the p.Arg219Gln variant is classified as pathogenic for congenital disorders of glycosylation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2022	Published functional studies demonstrate a damaging effect, specifically, R219Q is associated with significantly reduced mannose-6-phosphate isomerase activity compared to wild-type (Niehues et al., 1998); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24508628, 10980531, 26206375, 9525984, 18928705, 28928705, 24421398, 30545931, 11350186, 33204592, 31589614, 33643843, 33413482) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 09, 2021	DNA sequence analysis of the MPI gene demonstrated two sequence changes. The first sequence change, c.656G>A, in exon 5, results in an amino acid change, p.Arg219Gln. This sequence change has been described in gnomAD with a low population frequency of 0.029% (dbSNP rs104894489). The p.Arg219Gln change affects a highly conserved amino acid residue located in a domain of the MPI protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg219Gln substitution. This sequence change has been reported in the homozygous and compound heterozygous states in multiple individuals with features of congenital disorder of glycosylation (PMIDs: 10980531, 18928705, 11350186, 9525984). Functional studies have also demonstrated that the p.Arg219Gln change affects MPI protein function (PMID: 9525984, 24421398). Based on the collective evidence, the p.Arg219Gln variant is classified as pathogenic for congenital disorders of glycosylation -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;D;D;D;.;D;D;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D
Sift	Uncertain	0.0060	D;D;D;D;D;D;D;T
Sift4G	Benign	0.076	T;D;T;D;D;D;D;T
Polyphen		0.99	.;D;.;.;.;.;.;.
Vest4		0.91, 0.87, 0.88, 0.94, 0.90, 0.87, 0.69
MVP		0.94
MPC		0.77
ClinPred		0.50	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.80
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs104894489; hg19: chr15-75185647; COSMIC: COSV99075673; COSMIC: COSV99075673;