rs116933453

chr15-74897215-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002435.3(MPI):c.1049C>T(p.Thr350Met) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,613,980 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T350T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (10 hom.)
• Consequence: MPI NM_002435.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 6.19

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007683128).
• BP6: Variant 15-74897215-C-T is Benign according to our data. Variant chr15-74897215-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 94065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00133 (202/152262) while in subpopulation EAS AF= 0.02 (104/5188). AF 95% confidence interval is 0.0169. There are 3 homozygotes in gnomad4. There are 127 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPI	NM_002435.3	c.1049C>T	p.Thr350Met	missense_variant	7/8	ENST00000352410.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPI	ENST00000352410.9	c.1049C>T	p.Thr350Met	missense_variant	7/8	1	NM_002435.3	P1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152144 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0200

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00178 AC: 447 AN: 251356 Hom.: 2 AF XY: 0.00180 AC XY: 245 AN XY: 135854

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0183

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000976 AC: 1427 AN: 1461718 Hom.: 10 Cov.: 31 AF XY: 0.00104 AC XY: 754 AN XY: 727184

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0219

Gnomad4 SAS exome AF: 0.00158

Gnomad4 FIN exome AF: 0.000375

Gnomad4 NFE exome AF: 0.000263

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00133 AC: 202 AN: 152262 Hom.: 3 Cov.: 32 AF XY: 0.00171 AC XY: 127 AN XY: 74442

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0200

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00110 Hom.: 1

Bravo AF: 0.00122

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00189 AC: 230

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MPI-congenital disorder of glycosylation Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 09, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 22, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

MPI: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	20
Dann	Benign	0.94
DEOGEN2	Uncertain	0.70	D;.;D;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.75	T;T;T;T
MetaRNN	Benign	0.0077	T;T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.41	N;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.3	N;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.21	T;T;T;T
Sift4G	Benign	0.087	T;T;T;T
Polyphen		0.0070	B;.;.;B
Vest4		0.29
MVP		0.79
MPC		0.20
ClinPred		0.033	T
GERP RS		4.0
Varity_R		0.048
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs116933453; hg19: chr15-75189556;