NM_013335.4:c.118delC

Variant names:

• chr2-219500196-AC-A
• NM_013335.4:c.118delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_013335.4(GMPPA):​c.118delC​(p.His40IlefsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GMPPA NM_013335.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.830
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-219500196-AC-A is Pathogenic according to our data. Variant chr2-219500196-AC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2769661.Status of the report is criteria_provided_single_submitter, 1 stars.

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.118delC	p.His40IlefsTer30	frameshift	Exon 3 of 13	NP_037467.2
	GMPPA	NM_001438893.1		c.118delC	p.His40IlefsTer30	frameshift	Exon 3 of 12	NP_001425822.1
	GMPPA	NM_001438894.1		c.118delC	p.His40IlefsTer30	frameshift	Exon 3 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.118delC	p.His40IlefsTer30	frameshift	Exon 3 of 13	ENSP00000315925.6	Q96IJ6-1
	GMPPA	ENST00000358215.8	TSL:1	c.118delC	p.His40IlefsTer30	frameshift	Exon 3 of 13	ENSP00000350949.3	Q96IJ6-1
	GMPPA	ENST00000950500.1		c.118delC	p.His40IlefsTer30	frameshift	Exon 3 of 13	ENSP00000620559.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Alacrima, achalasia, and intellectual disability syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.83

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

hg19: chr2-220364918;