15-74893306-G-C

Variant names:

• chr15-74893306-G-C
• rs104894489
• NM_002435.3:c.656G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_002435.3(MPI):​c.656G>C​(p.Arg219Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R219Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MPI NM_002435.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-74893306-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPI	NM_002435.3	c.656G>C	p.Arg219Pro	missense_variant	Exon 5 of 8	ENST00000352410.9	NP_002426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPI	ENST00000352410.9	c.656G>C	p.Arg219Pro	missense_variant	Exon 5 of 8	1	NM_002435.3	ENSP00000318318.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;D;D;.;D;D;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	.;H;.;.;.;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.1	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0050	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.044	D;T;D;D;T;T;D;D
Polyphen		0.79	.;P;.;.;.;.;.;.
Vest4		0.88, 0.86, 0.89, 0.88, 0.87, 0.90, 0.80
MutPred		0.83		.;Loss of MoRF binding (P = 0.0032);Loss of MoRF binding (P = 0.0032);Loss of MoRF binding (P = 0.0032);.;.;.;Loss of MoRF binding (P = 0.0032);
MVP		0.93
MPC		0.81
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;