2-219504138-G-C

Variant names:

• chr2-219504138-G-C
• rs397518462
• NM_013335.4:c.545G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_013335.4(GMPPA):​c.545G>C​(p.Gly182Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. G182D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GMPPA NM_013335.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.82
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-219504138-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 88693.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMPPA	NM_013335.4	c.545G>C	p.Gly182Ala	missense_variant	Exon 7 of 13	ENST00000313597.10	NP_037467.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMPPA	ENST00000313597.10	c.545G>C	p.Gly182Ala	missense_variant	Exon 7 of 13	1	NM_013335.4	ENSP00000315925.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;D;D;D;D;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;.;.;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;H;H;H;.;H;.
PhyloP100		9.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.6	D;D;D;D;D;D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.97	D;D;D;D;.;D;.
Vest4		0.99
MutPred		0.92		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);.;Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		0.96
MPC		1.2
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.84
Mutation Taster		=8/92	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: rs397518462; hg19: chr2-220368860;