rs12593975

Variant names:

• chr15-74897250-G-A
• rs12593975
• NM_002435.3:c.1053+31G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002435.3(MPI):​c.1053+31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0846 in 1,606,660 control chromosomes in the GnomAD database, including 11,890 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (1053 hom., cov: 32)
  • Exomes 𝑓: 0.084 (10837 hom.)
• Consequence: MPI NM_002435.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.893
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Myriad Women’s Health, G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 15-74897250-G-A is Benign according to our data. Variant chr15-74897250-G-A is described in ClinVar as [Benign]. Clinvar id is 258656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPI	NM_002435.3	c.1053+31G>A		intron_variant	Intron 7 of 7	ENST00000352410.9	NP_002426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPI	ENST00000352410.9	c.1053+31G>A		intron_variant	Intron 7 of 7	1	NM_002435.3	ENSP00000318318.6

Frequencies

GnomAD3 genomes AF: 0.0865 AC: 13160 AN: 152086 Hom.: 1054 Cov.: 32

Gnomad AFR AF: 0.0623

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0657

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0514

Gnomad OTH AF: 0.0952

GnomAD2 exomes AF: 0.137 AC: 34169 AN: 250300 AF XY: 0.142

Gnomad AFR exome AF: 0.0642

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.0661

Gnomad EAS exome AF: 0.360

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.0529

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.0844 AC: 122786 AN: 1454456 Hom.: 10837 Cov.: 29 AF XY: 0.0913 AC XY: 66108 AN XY: 724056

African (AFR) AF: 0.0591 AC: 1972 AN: 33350

American (AMR) AF: 0.180 AC: 8053 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0661 AC: 1727 AN: 26110

East Asian (EAS) AF: 0.342 AC: 13561 AN: 39662

South Asian (SAS) AF: 0.336 AC: 28878 AN: 86068

European-Finnish (FIN) AF: 0.101 AC: 5348 AN: 53034

Middle Eastern (MID) AF: 0.0957 AC: 551 AN: 5758

European-Non Finnish (NFE) AF: 0.0511 AC: 56518 AN: 1105636

Other (OTH) AF: 0.103 AC: 6178 AN: 60150

GnomAD4 genome AF: 0.0865 AC: 13171 AN: 152204 Hom.: 1053 Cov.: 32 AF XY: 0.0952 AC XY: 7087 AN XY: 74406

African (AFR) AF: 0.0624 AC: 2591 AN: 41528

American (AMR) AF: 0.118 AC: 1801 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0657 AC: 228 AN: 3470

East Asian (EAS) AF: 0.353 AC: 1825 AN: 5174

South Asian (SAS) AF: 0.360 AC: 1735 AN: 4818

European-Finnish (FIN) AF: 0.109 AC: 1155 AN: 10600

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0514 AC: 3494 AN: 68004

Other (OTH) AF: 0.0956 AC: 202 AN: 2112

Alfa AF: 0.0715 Hom.: 239

Bravo AF: 0.0824

Asia WGS AF: 0.371 AC: 1287 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MPI-congenital disorder of glycosylation Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.48
DANN	Benign	0.83
PhyloP100		-0.89
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs12593975; hg19: chr15-75189591; COSMIC: COSV60396497; COSMIC: COSV60396497;