rs117089191

Variant names:

• chr15-74897148-C-T
• rs117089191
• NM_002435.3:c.982C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-74897148-C-T
• chr15-74897148-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002435.3(MPI):​c.982C>T​(p.Arg328Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0094 in 1,614,186 control chromosomes in the GnomAD database, including 101 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. R328R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0055 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (97 hom.)
• Consequence: MPI NM_002435.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.64
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074915886).
• BP6: Variant 15-74897148-C-T is Benign according to our data. Variant chr15-74897148-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00555 (845/152310) while in subpopulation NFE AF = 0.0109 (739/68028). AF 95% confidence interval is 0.0102. There are 4 homozygotes in GnomAd4. There are 357 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.982C>T	p.Arg328Trp	missense	Exon 7 of 8	NP_002426.1	P34949-1
	MPI	NM_001330372.2		c.922C>T	p.Arg308Trp	missense	Exon 7 of 8	NP_001317301.1	H3BPB8
	MPI	NM_001289156.2		c.832C>T	p.Arg278Trp	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.982C>T	p.Arg328Trp	missense	Exon 7 of 8	ENSP00000318318.6	P34949-1
	MPI	ENST00000323744.10	TSL:1	c.799C>T	p.Arg267Trp	missense	Exon 6 of 7	ENSP00000318192.6	P34949-2
	MPI	ENST00000566377.5	TSL:1	c.845-364C>T		intron	N/A	ENSP00000455405.1	H3BPP3

Frequencies

GnomAD3 genomes AF: 0.00556 AC: 846 AN: 152192 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00554 AC: 1394 AN: 251486 AF XY: 0.00552

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00291

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00586

GnomAD4 exome AF: 0.00980 AC: 14330 AN: 1461876 Hom.: 97 Cov.: 31 AF XY: 0.00923 AC XY: 6712 AN XY: 727240

African (AFR) AF: 0.00182 AC: 61 AN: 33480

American (AMR) AF: 0.00119 AC: 53 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00404 AC: 216 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0121 AC: 13492 AN: 1111996

Other (OTH) AF: 0.00831 AC: 502 AN: 60396

GnomAD4 genome AF: 0.00555 AC: 845 AN: 152310 Hom.: 4 Cov.: 32 AF XY: 0.00479 AC XY: 357 AN XY: 74474

African (AFR) AF: 0.00147 AC: 61 AN: 41570

American (AMR) AF: 0.000981 AC: 15 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0109 AC: 739 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00893 Hom.: 20

Bravo AF: 0.00527

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0156 AC: 60

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00908 AC: 78

ExAC AF: 0.00610 AC: 741

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0102

EpiControl AF: 0.00996

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	MPI-congenital disorder of glycosylation (3)
-	-	2	not specified (2)
-	-	1	MPI-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0075	T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.8	L
PhyloP100		1.6
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.052	T
Polyphen		0.021	B
Vest4		0.19
MVP		0.87
MPC		0.21
ClinPred		0.013	T
GERP RS		3.1
Varity_R		0.10
gMVP		0.44
Mutation Taster		=99/1	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: rs117089191; hg19: chr15-75189489; COSMIC: COSV99052309; COSMIC: COSV99052309;