chr2-219501903-C-G

Variant names:

• chr2-219501903-C-G
• rs397518460
• NM_013335.4:c.295C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_013335.4(GMPPA):​c.295C>G​(p.Arg99Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R99L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GMPPA NM_013335.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.52
• Publications: 4 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013335.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GMPPA	NM_013335.4	MANE Select	c.295C>G	p.Arg99Gly	missense	Exon 5 of 13	NP_037467.2
	GMPPA	NM_001438893.1		c.295C>G	p.Arg99Gly	missense	Exon 5 of 12	NP_001425822.1
	GMPPA	NM_001438894.1		c.295C>G	p.Arg99Gly	missense	Exon 5 of 12	NP_001425823.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GMPPA	ENST00000313597.10	TSL:1 MANE Select	c.295C>G	p.Arg99Gly	missense	Exon 5 of 13	ENSP00000315925.6	Q96IJ6-1
	GMPPA	ENST00000358215.8	TSL:1	c.295C>G	p.Arg99Gly	missense	Exon 5 of 13	ENSP00000350949.3	Q96IJ6-1
	GMPPA	ENST00000950500.1		c.295C>G	p.Arg99Gly	missense	Exon 5 of 13	ENSP00000620559.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.67		Loss of methylation at R99 (P = 0.0455)
MVP		0.96
MPC		1.4
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.96
gMVP		0.91
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs397518460; hg19: chr2-220366625;