15-74897148-C-G

Variant names:

• chr15-74897148-C-G
• rs117089191
• NM_002435.3:c.982C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002435.3(MPI):​c.982C>G​(p.Arg328Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign 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. R328W) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MPI NM_002435.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64
• Publications: 8 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.982C>G	p.Arg328Gly	missense	Exon 7 of 8	NP_002426.1	P34949-1
	MPI	NM_001330372.2		c.922C>G	p.Arg308Gly	missense	Exon 7 of 8	NP_001317301.1	H3BPB8
	MPI	NM_001289156.2		c.832C>G	p.Arg278Gly	missense	Exon 6 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.982C>G	p.Arg328Gly	missense	Exon 7 of 8	ENSP00000318318.6	P34949-1
	MPI	ENST00000323744.10	TSL:1	c.799C>G	p.Arg267Gly	missense	Exon 6 of 7	ENSP00000318192.6	P34949-2
	MPI	ENST00000566377.5	TSL:1	c.845-364C>G		intron	N/A	ENSP00000455405.1	H3BPP3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.3	L
PhyloP100		1.6
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.28
Sift	Benign	0.36	T
Sift4G	Benign	0.40	T
Polyphen		0.091	B
Vest4		0.27
MutPred		0.56		Loss of solvent accessibility (P = 0.0159)
MVP		0.81
MPC		0.26
ClinPred		0.10	T
GERP RS		3.1
Varity_R		0.15
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.81		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs117089191; hg19: chr15-75189489;