18-11884579-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_023075.6(MPPE1):c.1057C>T(p.Arg353Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: MPPE1 NM_023075.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.149

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07414347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPPE1	NM_023075.6	c.1057C>T	p.Arg353Cys	missense_variant	11/11	ENST00000588072.6
GNAL	NM_001369387.1	c.*3444G>A		3_prime_UTR_variant	12/12	ENST00000423027.8
GNAL	NM_182978.4	c.*3444G>A		3_prime_UTR_variant	12/12	ENST00000334049.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPPE1	ENST00000588072.6	c.1057C>T	p.Arg353Cys	missense_variant	11/11	1	NM_023075.6	P1
GNAL	ENST00000334049.11	c.*3444G>A		3_prime_UTR_variant	12/12	1	NM_182978.4
GNAL	ENST00000423027.8	c.*3444G>A		3_prime_UTR_variant	12/12	1	NM_001369387.1	P1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

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: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000722 AC: 18 AN: 249282 Hom.: 0 AF XY: 0.0000742 AC XY: 10 AN XY: 134858

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000894

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000930 AC: 136 AN: 1461628 Hom.: 0 Cov.: 31 AF XY: 0.0000811 AC XY: 59 AN XY: 727086

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000980

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74374

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000982

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000823 Hom.: 0

Bravo AF: 0.000314

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

The c.1057C>T (p.R353C) 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 1057, causing the arginine (R) at amino acid position 353 to be replaced by a cysteine (C). 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	0.11
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	9.1
Dann	Benign	0.79
DEOGEN2	Benign	0.0086	T;.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.85	T;.;T;D
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.074	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.19	T
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.017	B;B;B;.
Vest4		0.052
MVP		0.13
MPC		0.17
ClinPred		0.028	T
GERP RS		-7.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.58

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

Other links and lift over

dbSNP: rs144278251; hg19: chr18-11884578;