Genetic Variant MPI:p.Arg295Leu (chr15-74897050-G-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_002435.3(MPI):c.884G>T(p.Arg295Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. R295H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MPI
NM_002435.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.88

Publications

0 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Myriad Women’s Health, G2P, ClinGen

MPI links:

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ACMG classification

Classification was made for transcript

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 chr15-74897050-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 14349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MPI	NM_002435.3	MANE Select	c.884G>T	p.Arg295Leu	missense	Exon 7 of 8	NP_002426.1
MPI	NM_001330372.2		c.824G>T	p.Arg275Leu	missense	Exon 7 of 8	NP_001317301.1
MPI	NM_001289156.2		c.734G>T	p.Arg245Leu	missense	Exon 6 of 7	NP_001276085.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MPI	ENST00000352410.9	TSL:1 MANE Select	c.884G>T	p.Arg295Leu	missense	Exon 7 of 8	ENSP00000318318.6
MPI	ENST00000323744.10	TSL:1	c.701G>T	p.Arg234Leu	missense	Exon 6 of 7	ENSP00000318192.6
MPI	ENST00000566377.5	TSL:1	c.845-462G>T		intron	N/A	ENSP00000455405.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.5

PhyloP100

9.9

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.99

MutPred

0.94

Loss of catalytic residue at R295 (P = 0.0592)

MVP

0.99

MPC

0.84

ClinPred

1.0

GERP RS

5.0

Varity_R

0.93

gMVP

0.94

Mutation Taster

=4/96

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over