Genetic Variant GMPPA:p.Met36Ile (chr2-219500188-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_013335.4(GMPPA):c.108G>A(p.Met36Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,429,988 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M36V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

GMPPA
NM_013335.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.46

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMPPA	NM_013335.4 link	c.108G>A	p.Met36Ile	missense_variant	Exon 3 of 13	ENST00000313597.10	NP_037467.2	Q96IJ6-1A0A384MDS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMPPA	ENST00000313597.10 link	c.108G>A	p.Met36Ile	missense_variant	Exon 3 of 13	1	NM_013335.4	ENSP00000315925.6		Q96IJ6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000500

AC:

AN:

199942

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000344

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

6.99e-7

AC:

AN:

1429988

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

708466

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33118

American (AMR)

AF:

0.0000249

AC:

AN:

40132

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25620

East Asian (EAS)

AF:

0.00

AC:

AN:

38868

South Asian (SAS)

AF:

0.00

AC:

AN:

82806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51238

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1093292

Other (OTH)

AF:

0.00

AC:

AN:

59188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.45

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

Eigen

Benign

-0.12

Eigen_PC

Benign

0.076

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

.;D;.;.;D;D;D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.34

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

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.32

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

PhyloP100

7.5

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

0.49

GERP RS

4.3

PromoterAI

0.014

Neutral

(source)

Varity_R

0.39

gMVP

0.82

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over