15-74890555-G-C

Variant names:

• chr15-74890555-G-C
• rs371649838
• NM_002435.3:c.45G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002435.3(MPI):​c.45G>C​(p.Gln15His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MPI NM_002435.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.196
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28611025).

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.45G>C	p.Gln15His	missense	Exon 2 of 8	NP_002426.1	P34949-1
	MPI	NM_001289157.2		c.45G>C	p.Gln15His	missense	Exon 2 of 7	NP_001276086.1	P34949-2
	MPI	NM_001289155.2		c.45G>C	p.Gln15His	missense	Exon 2 of 7	NP_001276084.1	H3BPP3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPI	ENST00000352410.9	TSL:1 MANE Select	c.45G>C	p.Gln15His	missense	Exon 2 of 8	ENSP00000318318.6	P34949-1
	MPI	ENST00000323744.10	TSL:1	c.45G>C	p.Gln15His	missense	Exon 2 of 7	ENSP00000318192.6	P34949-2
	MPI	ENST00000563422.5	TSL:1	c.45G>C	p.Gln15His	missense	Exon 2 of 6	ENSP00000457885.1	H3BUZ9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	MPI-congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.015	N
PhyloP100		-0.20
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.51	N
REVEL	Uncertain	0.36
Sift	Benign	0.27	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.52		Loss of ubiquitination at K20 (P = 0.0546)
MVP		0.79
MPC		0.18
ClinPred		0.21	T
GERP RS		-0.49
PromoterAI		0.0052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.47
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs371649838; hg19: chr15-75182896;