2-219500188-G-C

Position:

chr2-219500188-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_013335.4(GMPPA):c.108G>C(p.Met36Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,582,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

GMPPA
NM_013335.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.46

Variant links:

Genes affected

GMPPA (HGNC:22923): (GDP-mannose pyrophosphorylase A) This gene is thought to encode a GDP-mannose pyrophosphorylase. This enzyme catalyzes the reaction which converts mannose-1-phosphate and GTP to GDP-mannose which is involved in the production of N-linked oligosaccharides. [provided by RefSeq, Jul 2008]

GMPPA links:

ASIC4-AS1 (HGNC:40960): (ASIC4 antisense RNA 1)

ASIC4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4104281).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GMPPA	NM_013335.4 linkuse as main transcript	c.108G>C	p.Met36Ile	missense_variant	3/13	ENST00000313597.10
ASIC4-AS1	XR_923921.2 linkuse as main transcript	n.391+16508C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GMPPA	ENST00000313597.10 linkuse as main transcript	c.108G>C	p.Met36Ile	missense_variant	3/13	1	NM_013335.4	P1	Q96IJ6-1
ASIC4-AS1	ENST00000429882.1 linkuse as main transcript	n.182+16508C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000700

AC:

AN:

199942

Hom.:

AF XY:

0.0000655

AC XY:

AN XY:

106884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000166

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000176

AC:

252

AN:

1429986

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

120

AN XY:

708466

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.000228

Gnomad4 OTH exome

AF:

0.0000507

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000497

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

The c.108G>C (p.M36I) alteration is located in exon 3 (coding exon 2) of the GMPPA gene. This alteration results from a G to C substitution at nucleotide position 108, causing the methionine (M) at amino acid position 36 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Alacrima, achalasia, and intellectual disability syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 11, 2018

This sequence change replaces methionine with isoleucine at codon 36 of the GMPPA protein (p.Met36Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs745438072, ExAC 0.02%). This variant has not been reported in the literature in individuals with GMPPA-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

T;.;T;T;.;T;T;.

Eigen

Benign

-0.12

Eigen_PC

Benign

0.076

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.021

MetaRNN

Benign

0.25

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.32

N;N;N;N;.;.;N;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.75

N;N;N;N;N;N;N;.

REVEL

Uncertain

0.36

Sift

Benign

0.97

T;T;T;T;T;T;T;.

Sift4G

Benign

0.68

T;T;T;T;T;T;T;T

Polyphen

0.0090

B;B;B;B;.;.;B;.

Vest4

0.85

MutPred

0.50

Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);.;Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);

MVP

0.65

MPC

0.44

ClinPred

0.18

GERP RS

4.3

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.39

gMVP

0.82

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