18-11884519-G-A

Position:

chr18-11884519-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_023075.6(MPPE1):c.1117C>T(p.Leu373Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,166 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

MPPE1
NM_023075.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.325

Variant links:

Genes affected

MPPE1 (HGNC:15988): (metallophosphoesterase 1) Predicted to enable GPI anchor binding activity; GPI-mannose ethanolamine phosphate phosphodiesterase activity; and manganese ion binding activity. Involved in GPI anchor biosynthetic process. Located in Golgi apparatus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MPPE1 links:

GNAL (HGNC:4388): (G protein subunit alpha L) This gene encodes a stimulatory G protein alpha subunit which mediates odorant signaling in the olfactory epithelium. This protein couples dopamine type 1 receptors and adenosine A2A receptors and is widely expressed in the central nervous system. Mutations in this gene have been associated with dystonia 25 and this gene is located in a susceptibility region for bipolar disorder and schizophrenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

GNAL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02924788).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MPPE1	NM_023075.6 linkuse as main transcript	c.1117C>T	p.Leu373Phe	missense_variant	11/11	ENST00000588072.6	NP_075563.3
GNAL	NM_001369387.1 linkuse as main transcript	c.*3384G>A		3_prime_UTR_variant	12/12	ENST00000423027.8	NP_001356316.1
GNAL	NM_182978.4 linkuse as main transcript	c.*3384G>A		3_prime_UTR_variant	12/12	ENST00000334049.11	NP_892023.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPPE1	ENST00000588072.6 linkuse as main transcript	c.1117C>T	p.Leu373Phe	missense_variant	11/11	1	NM_023075.6	ENSP00000465894	P1	Q53F39-1
GNAL	ENST00000334049.11 linkuse as main transcript	c.*3384G>A		3_prime_UTR_variant	12/12	1	NM_182978.4	ENSP00000334051		P38405-2
GNAL	ENST00000423027.8 linkuse as main transcript	c.*3384G>A		3_prime_UTR_variant	12/12	1	NM_001369387.1	ENSP00000408489	P1	P38405-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251150

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000118

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000283

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2023

The c.1117C>T (p.L373F) alteration is located in exon 11 (coding exon 9) of the MPPE1 gene. This alteration results from a C to T substitution at nucleotide position 1117, causing the leucine (L) at amino acid position 373 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.8

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0046

T;.;.;T

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.80

T;.;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.029

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.2

M;.;.;.

MutationTaster

Benign

0.74

N;N;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.0

.;N;.;.

REVEL

Benign

0.074

Sift

Uncertain

0.022

.;D;.;.

Sift4G

Uncertain

0.017

D;D;D;D

Polyphen

1.0

D;B;B;.

Vest4

0.10

MutPred

0.45

Gain of catalytic residue at L373 (P = 0.0377);.;.;.;

MVP

0.29

MPC

0.21

ClinPred

0.11

GERP RS

-2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.69

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over