NM_002435.3:c.684C>T

Variant names:

• chr15-74896165-C-T
• rs139190144
• NM_002435.3:c.684C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002435.3(MPI):​c.684C>T​(p.Asn228Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0281 in 1,614,080 control chromosomes in the GnomAD database, including 886 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (60 hom., cov: 32)
  • Exomes 𝑓: 0.029 (826 hom.)
• Consequence: MPI NM_002435.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.96
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 15-74896165-C-T is Benign according to our data. Variant chr15-74896165-C-T is described in ClinVar as Benign. ClinVar VariationId is 167305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.96 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0635 is higher than 0.05.

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.684C>T	p.Asn228Asn	synonymous	Exon 6 of 8	NP_002426.1	P34949-1
	MPI	NM_001330372.2		c.624C>T	p.Asn208Asn	synonymous	Exon 6 of 8	NP_001317301.1	H3BPB8
	MPI	NM_001289156.2		c.534C>T	p.Asn178Asn	synonymous	Exon 5 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.684C>T	p.Asn228Asn	synonymous	Exon 6 of 8	ENSP00000318318.6	P34949-1
	MPI	ENST00000323744.10	TSL:1	c.501C>T	p.Asn167Asn	synonymous	Exon 5 of 7	ENSP00000318192.6	P34949-2
	MPI	ENST00000563422.5	TSL:1	c.684C>T	p.Asn228Asn	synonymous	Exon 6 of 6	ENSP00000457885.1	H3BUZ9

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 3240 AN: 152140 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.00490

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0689

Gnomad FIN AF: 0.0395

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0281

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0254 AC: 6388 AN: 251398 AF XY: 0.0287

Gnomad AFR exome AF: 0.00492

Gnomad AMR exome AF: 0.00809

Gnomad ASJ exome AF: 0.00804

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0352

Gnomad NFE exome AF: 0.0268

Gnomad OTH exome AF: 0.0213

GnomAD4 exome AF: 0.0288 AC: 42143 AN: 1461822 Hom.: 826 Cov.: 31 AF XY: 0.0301 AC XY: 21902 AN XY: 727204

African (AFR) AF: 0.00424 AC: 142 AN: 33480

American (AMR) AF: 0.00941 AC: 421 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00650 AC: 170 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0665 AC: 5740 AN: 86258

European-Finnish (FIN) AF: 0.0356 AC: 1902 AN: 53404

Middle Eastern (MID) AF: 0.0252 AC: 145 AN: 5758

European-Non Finnish (NFE) AF: 0.0289 AC: 32160 AN: 1111974

Other (OTH) AF: 0.0241 AC: 1457 AN: 60388

GnomAD4 genome AF: 0.0213 AC: 3242 AN: 152258 Hom.: 60 Cov.: 32 AF XY: 0.0225 AC XY: 1677 AN XY: 74438

African (AFR) AF: 0.00488 AC: 203 AN: 41558

American (AMR) AF: 0.0141 AC: 216 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.0696 AC: 336 AN: 4826

European-Finnish (FIN) AF: 0.0395 AC: 419 AN: 10602

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0281 AC: 1911 AN: 68014

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0227 Hom.: 36

Bravo AF: 0.0175

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.0293

EpiControl AF: 0.0260

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.78
PhyloP100		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs139190144; hg19: chr15-75188506; COSMIC: COSV107396476; COSMIC: COSV107396476;