rs116933453

Variant names:

• chr15-74897215-C-T
• rs116933453
• NM_002435.3:c.1049C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-74897215-C-T
• chr15-74897215-C-A
• chr15-74897215-C-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 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. 13/21 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
• Publications: 5 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: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_002435.3
• 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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.1049C>T	p.Thr350Met	missense	Exon 7 of 8	NP_002426.1	P34949-1
	MPI	NM_001330372.2		c.989C>T	p.Thr330Met	missense	Exon 7 of 8	NP_001317301.1	H3BPB8
	MPI	NM_001289156.2		c.899C>T	p.Thr300Met	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.1049C>T	p.Thr350Met	missense	Exon 7 of 8	ENSP00000318318.6	P34949-1
	MPI	ENST00000323744.10	TSL:1	c.866C>T	p.Thr289Met	missense	Exon 6 of 7	ENSP00000318192.6	P34949-2
	MPI	ENST00000566377.5	TSL:1	c.845-297C>T		intron	N/A	ENSP00000455405.1	H3BPP3

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

GnomAD2 exomes AF: 0.00178 AC: 447 AN: 251356 AF XY: 0.00180

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 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

African (AFR) AF: 0.000448 AC: 15 AN: 33476

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0219 AC: 871 AN: 39698

South Asian (SAS) AF: 0.00158 AC: 136 AN: 86252

European-Finnish (FIN) AF: 0.000375 AC: 20 AN: 53384

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000263 AC: 292 AN: 1111896

Other (OTH) AF: 0.00136 AC: 82 AN: 60386

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

African (AFR) AF: 0.000650 AC: 27 AN: 41550

American (AMR) AF: 0.000262 AC: 4 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0200 AC: 104 AN: 5188

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4828

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00110 Hom.: 2

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	MPI-congenital disorder of glycosylation (4)
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0077	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.41	N
PhyloP100		6.2
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.3	N
REVEL	Uncertain	0.31
Sift	Benign	0.21	T
Sift4G	Benign	0.087	T
Polyphen		0.0070	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
Mutation Taster		=100/0	polymorphism

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: rs116933453; hg19: chr15-75189556;