Variant 2-219500213-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_013335.4(GMPPA):c.133G>A(p.Ala45Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GMPPA
NM_013335.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.39

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 made for transcript

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=0.25026715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GMPPA	NM_013335.4 linkuse as main transcript	c.133G>A	p.Ala45Thr	missense_variant	3/13	ENST00000313597.10	NP_037467.2
ASIC4-AS1	XR_923921.2 linkuse as main transcript	n.391+16483C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GMPPA	ENST00000313597.10 linkuse as main transcript	c.133G>A	p.Ala45Thr	missense_variant	3/13	1	NM_013335.4	ENSP00000315925	P1	Q96IJ6-1
ASIC4-AS1	ENST00000429882.1 linkuse as main transcript	n.182+16483C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1403496

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

694930

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.133G>A (p.A45T) alteration is located in exon 3 (coding exon 2) of the GMPPA gene. This alteration results from a G to A substitution at nucleotide position 133, causing the alanine (A) at amino acid position 45 to be replaced by a threonine (T). 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

0.092

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.49

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

Eigen

Benign

-0.079

Eigen_PC

Benign

0.082

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.89

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

M_CAP

Benign

0.029

MetaRNN

Benign

0.25

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

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.5

L;L;L;L;.;.;L;.

MutationTaster

Benign

0.85

D;D;D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.35

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

REVEL

Benign

0.10

Sift

Benign

0.26

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

Sift4G

Benign

0.25

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

Polyphen

0.0010

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

Vest4

0.25

MutPred

0.46

Gain of glycosylation at A45 (P = 0.0593);Gain of glycosylation at A45 (P = 0.0593);Gain of glycosylation at A45 (P = 0.0593);Gain of glycosylation at A45 (P = 0.0593);Gain of glycosylation at A45 (P = 0.0593);.;Gain of glycosylation at A45 (P = 0.0593);Gain of glycosylation at A45 (P = 0.0593);

MVP

0.80

MPC

0.38

ClinPred

0.57

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.095

gMVP

0.51

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