2-219500188-G-A

Position:

• chr2-219500188-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_013335.4(GMPPA):​c.108G>A​(p.Met36Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,429,988 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GMPPA NM_013335.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.46

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GMPPA	NM_013335.4	c.108G>A	p.Met36Ile	missense_variant	3/13	ENST00000313597.10	NP_037467.2
ASIC4-AS1	XR_923921.2	n.391+16508C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GMPPA	ENST00000313597.10	c.108G>A	p.Met36Ile	missense_variant	3/13	1	NM_013335.4	ENSP00000315925	P1
ASIC4-AS1	ENST00000429882.1	n.182+16508C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000500 AC: 1 AN: 199942 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 106884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000344

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1429988 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 708466

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000249

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T;.;T;T;.;T;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	.;D;.;.;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.32	N;N;N;N;.;.;N;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.75	N;N;N;N;N;N;N;.
REVEL	Uncertain	0.36
Sift	Benign	0.97	T;T;T;T;T;T;T;.
Sift4G	Benign	0.68	T;T;T;T;T;T;T;T
Polyphen		0.0090	B;B;B;B;.;.;B;.
Vest4		0.85
MutPred		0.50		Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);.;Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);
MVP		0.65
MPC		0.44
ClinPred		0.49	T
GERP RS		4.3
Varity_R		0.39
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs745438072; hg19: chr2-220364910;