chr15-74893306-G-A

Variant names:

• chr15-74893306-G-A
• rs104894489
• NM_002435.3:c.656G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PP5_Very_Strong

The NM_002435.3(MPI):​c.656G>A​(p.Arg219Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000393945: Expression studies in COS-7 cells showed that the variant protein resulted in MPI activity indistinguishable from background, while expression of normal MPI increased specific activity approximately 10 fold when compared with controls (Niehues et al. 1998).; SCV000962921: Experimental studies have shown that this missense change affects MPI function (PMID:9525984, 24421398).; SCV002069686: Functional studies have also demonstrated that the p.Arg219Gln change affects MPI protein function (PMID:9525984, 24421398).; SCV002504183: Published functional studies demonstrate a damaging effect, specifically, R219Q is associated with significantly reduced mannose-6-phosphate isomerase activity compared to wild-type (Niehues et al., 1998).". Synonymous variant affecting the same amino acid position (i.e. R219R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: MPI NM_002435.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.62
• Publications: 18 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: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000393945: Expression studies in COS-7 cells showed that the variant protein resulted in MPI activity indistinguishable from background, while expression of normal MPI increased specific activity approximately 10 fold when compared with controls (Niehues et al. 1998).; SCV000962921: Experimental studies have shown that this missense change affects MPI function (PMID: 9525984, 24421398).; SCV002069686: Functional studies have also demonstrated that the p.Arg219Gln change affects MPI protein function (PMID: 9525984, 24421398).; SCV002504183: Published functional studies demonstrate a damaging effect, specifically, R219Q is associated with significantly reduced mannose-6-phosphate isomerase activity compared to wild-type (Niehues et al., 1998).
• PP5: Variant 15-74893306-G-A is Pathogenic according to our data. Variant chr15-74893306-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 14345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.656G>A	p.Arg219Gln	missense	Exon 5 of 8	NP_002426.1	P34949-1
	MPI	NM_001330372.2		c.596G>A	p.Arg199Gln	missense	Exon 5 of 8	NP_001317301.1	H3BPB8
	MPI	NM_001289156.2		c.506G>A	p.Arg169Gln	missense	Exon 4 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.656G>A	p.Arg219Gln	missense	Exon 5 of 8	ENSP00000318318.6	P34949-1
	MPI	ENST00000563422.5	TSL:1	c.656G>A	p.Arg219Gln	missense	Exon 5 of 6	ENSP00000457885.1	H3BUZ9
	MPI	ENST00000566377.5	TSL:1	c.656G>A	p.Arg219Gln	missense	Exon 5 of 7	ENSP00000455405.1	H3BPP3

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000291 AC: 73 AN: 250746 AF XY: 0.000295

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000540

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000276 AC: 403 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.000270 AC XY: 196 AN XY: 727240

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000449 AC: 24 AN: 53420

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

European-Non Finnish (NFE) AF: 0.000314 AC: 349 AN: 1111996

Other (OTH) AF: 0.000381 AC: 23 AN: 60396

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74364

African (AFR) AF: 0.0000724 AC: 3 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68042

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000256 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000453 AC: 55

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	MPI-congenital disorder of glycosylation (7)
2	-	-	not provided (2)
1	-	-	MPI-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.076	T
Polyphen		0.99	D
Vest4		0.91
MVP		0.94
MPC		0.77
ClinPred		0.50	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.80
gMVP		0.84
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs104894489; hg19: chr15-75185647; COSMIC: COSV99075673; COSMIC: COSV99075673;