chr2-219506260-A-C

Position:

• chr2-219506260-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_013335.4(GMPPA):​c.1000A>C​(p.Thr334Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T334M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GMPPA NM_013335.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.16

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]

GMPPA (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778
• PP5: Variant 2-219506260-A-C is Pathogenic according to our data. Variant chr2-219506260-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 88692.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GMPPA	NM_013335.4	c.1000A>C	p.Thr334Pro	missense_variant	12/13	ENST00000313597.10	NP_037467.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GMPPA	ENST00000313597.10	c.1000A>C	p.Thr334Pro	missense_variant	12/13	1	NM_013335.4	ENSP00000315925.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Alacrima, achalasia, and intellectual disability syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 03, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.;D;D;D;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	.;D;.;.;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	1.9	L;.;L;L;L;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.4	N;D;N;N;N;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0080	D;D;D;D;D;.
Sift4G	Uncertain	0.017	D;D;D;D;D;D
Polyphen		0.90	P;P;P;P;P;.
Vest4		0.68
MutPred		0.70		Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.89
MPC		0.75
ClinPred		0.73	D
GERP RS		3.3
Varity_R		0.26
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397518461; hg19: chr2-220370982;