18-11884459-G-A

Position:

• chr18-11884459-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_023075.6(MPPE1):​c.1177C>T​(p.Arg393Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,613,912 control chromosomes in the GnomAD database, including 6 homozygotes. 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 0.00083 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (5 hom.)
• Consequence: MPPE1 NM_023075.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010490179).
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPPE1	NM_023075.6	c.1177C>T	p.Arg393Cys	missense_variant	11/11	ENST00000588072.6
GNAL	NM_001369387.1	c.*3324G>A		3_prime_UTR_variant	12/12	ENST00000423027.8
GNAL	NM_182978.4	c.*3324G>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.1177C>T	p.Arg393Cys	missense_variant	11/11	1	NM_023075.6	P1
GNAL	ENST00000334049.11	c.*3324G>A		3_prime_UTR_variant	12/12	1	NM_182978.4
GNAL	ENST00000423027.8	c.*3324G>A		3_prime_UTR_variant	12/12	1	NM_001369387.1	P1

Frequencies

GnomAD3 genomes AF: 0.000835 AC: 127 AN: 152068 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000740 AC: 186 AN: 251212 Hom.: 1 AF XY: 0.000722 AC XY: 98 AN XY: 135786

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00125 AC: 1822 AN: 1461726 Hom.: 5 Cov.: 31 AF XY: 0.00119 AC XY: 868 AN XY: 727156

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000475

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00151

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000835 AC: 127 AN: 152186 Hom.: 1 Cov.: 33 AF XY: 0.000780 AC XY: 58 AN XY: 74400

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00129 Hom.: 0

Bravo AF: 0.000820

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000651 AC: 79

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00119

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

Sep 30, 2021

The c.1177C>T (p.R393C) 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 1177, causing the arginine (R) at amino acid position 393 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	0.091
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0035	T;.;.;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.82	T;.;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.24	T
Sift4G	Uncertain	0.030	D;D;D;D
Polyphen		0.96	D;P;P;.
Vest4		0.079
MVP		0.39
MPC		0.25
ClinPred		0.038	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.54

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: rs151247671; hg19: chr18-11884458; COSMIC: COSV99304384; COSMIC: COSV99304384;