NM_013335.4:c.1000A>G

Variant names:

• chr2-219506260-A-G
• rs397518461
• NM_013335.4:c.1000A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_013335.4(GMPPA):​c.1000A>G​(p.Thr334Ala) 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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T334P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GMPPA NM_013335.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.16
• Publications: 2 publications found

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

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

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-219506260-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 88692.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22954234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMPPA	NM_013335.4	c.1000A>G	p.Thr334Ala	missense_variant	Exon 12 of 13	ENST00000313597.10	NP_037467.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMPPA	ENST00000313597.10	c.1000A>G	p.Thr334Ala	missense_variant	Exon 12 of 13	1	NM_013335.4	ENSP00000315925.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Benign	0.75
DEOGEN2	Benign	0.24	T;.;T;T;T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	.;D;.;.;D;D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.23	T;T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	-0.40	N;.;N;N;N;.
PhyloP100		4.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.060	N;N;N;N;N;.
REVEL	Benign	0.26
Sift	Benign	1.0	T;T;T;T;T;.
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0020	B;B;B;B;B;.
Vest4		0.54
MutPred		0.64		Loss of catalytic residue at T334 (P = 0.0626);.;Loss of catalytic residue at T334 (P = 0.0626);Loss of catalytic residue at T334 (P = 0.0626);Loss of catalytic residue at T334 (P = 0.0626);Loss of catalytic residue at T334 (P = 0.0626);
MVP		0.77
MPC		0.38
ClinPred		0.24	T
GERP RS		3.3
Varity_R		0.031
gMVP		0.67
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs397518461; hg19: chr2-220370982;