rs759385120

Variant names:

• chr15-74890087-G-C
• rs759385120
• NM_002435.3:c.14G>C

Your query was ambiguous. Multiple possible variants found:

• chr15-74890087-G-C
• chr15-74890087-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002435.3(MPI):​c.14G>C​(p.Arg5Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,455,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MPI NM_002435.3 missense, splice_region
• Scores: Splicing: ADA: 0.00005535
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0330
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Myriad Women’s Health, G2P, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19278166).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPI	NM_002435.3	c.14G>C	p.Arg5Pro	missense_variant, splice_region_variant	Exon 1 of 8	ENST00000352410.9	NP_002426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPI	ENST00000352410.9	c.14G>C	p.Arg5Pro	missense_variant, splice_region_variant	Exon 1 of 8	1	NM_002435.3	ENSP00000318318.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1455834 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 724572

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111940

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	14
DANN	Benign	0.69
DEOGEN2	Uncertain	0.52	D;T;.;.;T;T;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.069	T
MutationAssessor	Benign	0.030	N;.;.;.;.;.;.;N;.;.
PhyloP100		0.033
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.1	N;N;D;D;D;N;D;N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.077	T;T;T;T;T;T;D;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010	B;.;.;.;.;.;.;B;.;.
Vest4		0.54
MutPred		0.43		Gain of glycosylation at R5 (P = 0.0151);Gain of glycosylation at R5 (P = 0.0151);Gain of glycosylation at R5 (P = 0.0151);Gain of glycosylation at R5 (P = 0.0151);Gain of glycosylation at R5 (P = 0.0151);Gain of glycosylation at R5 (P = 0.0151);Gain of glycosylation at R5 (P = 0.0151);Gain of glycosylation at R5 (P = 0.0151);Gain of glycosylation at R5 (P = 0.0151);Gain of glycosylation at R5 (P = 0.0151);
MVP		0.58
MPC		0.27
ClinPred		0.076	T
GERP RS		-0.43
PromoterAI		-0.35	Neutral
Varity_R		0.34
gMVP		0.64
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000055
dbscSNV1_RF	Benign	0.010
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: rs759385120; hg19: chr15-75182428; COSMIC: COSV100086325; COSMIC: COSV100086325;