15-74893306-G-C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• Publications: 18 publications found

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]

MPI Gene-Disease associations (from GenCC):

• MPI-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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 ClinVar as Pathogenic. ClinVar VariationId is 14345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002435.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPI	NM_002435.3	MANE Select	c.656G>C	p.Arg219Pro	missense	Exon 5 of 8	NP_002426.1	P34949-1
	MPI	NM_001330372.2		c.596G>C	p.Arg199Pro	missense	Exon 5 of 8	NP_001317301.1	H3BPB8
	MPI	NM_001289156.2		c.506G>C	p.Arg169Pro	missense	Exon 4 of 7	NP_001276085.1	F5GX71

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPI	ENST00000352410.9	TSL:1 MANE Select	c.656G>C	p.Arg219Pro	missense	Exon 5 of 8	ENSP00000318318.6	P34949-1
	MPI	ENST00000563422.5	TSL:1	c.656G>C	p.Arg219Pro	missense	Exon 5 of 6	ENSP00000457885.1	H3BUZ9
	MPI	ENST00000566377.5	TSL:1	c.656G>C	p.Arg219Pro	missense	Exon 5 of 7	ENSP00000455405.1	H3BPP3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		9.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.044	D
Polyphen		0.79	P
Vest4		0.88
MutPred		0.83		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

Other links and lift over

dbSNP: rs104894489; hg19: chr15-75185647;