2-219501561-A-C

Position:

• chr2-219501561-A-C

Variant summary

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

The NM_013335.4(GMPPA):​c.224A>C​(p.Glu75Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GMPPA NM_013335.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.07

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	UniProt
GMPPA	NM_013335.4	c.224A>C	p.Glu75Ala	missense_variant	4/13	ENST00000313597.10
ASIC4-AS1	XR_923921.2	n.391+15135T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GMPPA	ENST00000313597.10	c.224A>C	p.Glu75Ala	missense_variant	4/13	1	NM_013335.4	P1
ASIC4-AS1	ENST00000429882.1	n.182+15135T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2024

The c.224A>C (p.E75A) alteration is located in exon 4 (coding exon 3) of the GMPPA gene. This alteration results from a A to C substitution at nucleotide position 224, causing the glutamic acid (E) at amino acid position 75 to be replaced by an alanine (A). 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	0.10
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;.;D;D;.;D;D;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D;.;.;D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.1	L;L;L;L;.;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D;D;.
REVEL	Uncertain	0.43
Sift	Benign	0.052	T;T;T;T;D;T;T;.
Sift4G	Benign	0.061	T;T;T;T;T;T;T;D
Polyphen		0.24	B;P;B;B;.;.;B;.
Vest4		0.43
MutPred		0.38		Loss of solvent accessibility (P = 0.1459);Loss of solvent accessibility (P = 0.1459);Loss of solvent accessibility (P = 0.1459);Loss of solvent accessibility (P = 0.1459);Loss of solvent accessibility (P = 0.1459);.;Loss of solvent accessibility (P = 0.1459);Loss of solvent accessibility (P = 0.1459);
MVP		0.75
MPC		0.83
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.70

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: rs924595000; hg19: chr2-220366283;