rs1130741

Variant names:

• chr15-74897589-A-G
• rs1130741
• NM_002435.3:c.1131A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-74897589-A-G
• chr15-74897589-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000352410.9(MPI):​c.1131A>G​(p.Val377Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.509 in 1,613,846 control chromosomes in the GnomAD database, including 219,264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16292 hom., cov: 32)
  • Exomes 𝑓: 0.52 (202972 hom.)
• Consequence: MPI ENST00000352410.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.478
• Publications: 39 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 15-74897589-A-G is Benign according to our data. Variant chr15-74897589-A-G is described in ClinVar as Benign. ClinVar VariationId is 94066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.478 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000352410.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPI	NM_002435.3	MANE Select	c.1131A>G	p.Val377Val	synonymous	Exon 8 of 8	NP_002426.1
	MPI	NM_001330372.2		c.1071A>G	p.Val357Val	synonymous	Exon 8 of 8	NP_001317301.1
	MPI	NM_001289156.2		c.981A>G	p.Val327Val	synonymous	Exon 7 of 7	NP_001276085.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPI	ENST00000352410.9	TSL:1 MANE Select	c.1131A>G	p.Val377Val	synonymous	Exon 8 of 8	ENSP00000318318.6
	MPI	ENST00000323744.10	TSL:1	c.948A>G	p.Val316Val	synonymous	Exon 7 of 7	ENSP00000318192.6
	MPI	ENST00000566377.5	TSL:1	c.*58A>G		3_prime_UTR	Exon 7 of 7	ENSP00000455405.1

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68180 AN: 151932 Hom.: 16271 Cov.: 32

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.515

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.442

GnomAD2 exomes AF: 0.445 AC: 111822 AN: 251392 AF XY: 0.435

Gnomad AFR exome AF: 0.332

Gnomad AMR exome AF: 0.520

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.220

Gnomad FIN exome AF: 0.432

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.473

GnomAD4 exome AF: 0.515 AC: 753438 AN: 1461796 Hom.: 202972 Cov.: 55 AF XY: 0.505 AC XY: 367431 AN XY: 727218

African (AFR) AF: 0.331 AC: 11067 AN: 33480

American (AMR) AF: 0.523 AC: 23365 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 12220 AN: 26136

East Asian (EAS) AF: 0.245 AC: 9730 AN: 39698

South Asian (SAS) AF: 0.208 AC: 17946 AN: 86258

European-Finnish (FIN) AF: 0.438 AC: 23399 AN: 53418

Middle Eastern (MID) AF: 0.407 AC: 2348 AN: 5768

European-Non Finnish (NFE) AF: 0.561 AC: 624200 AN: 1111926

Other (OTH) AF: 0.483 AC: 29163 AN: 60396

GnomAD4 genome AF: 0.449 AC: 68256 AN: 152050 Hom.: 16292 Cov.: 32 AF XY: 0.439 AC XY: 32586 AN XY: 74308

African (AFR) AF: 0.339 AC: 14081 AN: 41486

American (AMR) AF: 0.515 AC: 7869 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 1627 AN: 3470

East Asian (EAS) AF: 0.230 AC: 1189 AN: 5172

South Asian (SAS) AF: 0.192 AC: 925 AN: 4816

European-Finnish (FIN) AF: 0.430 AC: 4538 AN: 10546

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.538 AC: 36573 AN: 67962

Other (OTH) AF: 0.443 AC: 937 AN: 2114

Alfa AF: 0.502 Hom.: 59839

Bravo AF: 0.458

Asia WGS AF: 0.229 AC: 800 AN: 3478

EpiCase AF: 0.524

EpiControl AF: 0.524

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	MPI-congenital disorder of glycosylation (5)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.4
DANN	Benign	0.68
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism (auto)

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: rs1130741; hg19: chr15-75189930; COSMIC: COSV60396702; COSMIC: COSV60396702;