NM_013335.4:c.133G>A

Variant names:

• chr2-219500213-G-A
• rs374902505
• NM_013335.4:c.133G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.39

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]

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

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=0.25026715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMPPA	NM_013335.4	c.133G>A	p.Ala45Thr	missense_variant	Exon 3 of 13	ENST00000313597.10	NP_037467.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMPPA	ENST00000313597.10	c.133G>A	p.Ala45Thr	missense_variant	Exon 3 of 13	1	NM_013335.4	ENSP00000315925.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1403496 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 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.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
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	D
LIST_S2	Uncertain	0.89	.;D;.;.;D;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.5	L;L;L;L;.;.;L;.
PrimateAI	Uncertain	0.55	T
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	D
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

Other links and lift over

dbSNP: rs374902505; hg19: chr2-220364935;