chr2-219501545-GA-G

Variant names:

• chr2-219501545-GA-G
• rs886037654
• NM_013335.4:c.210delA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_013335.4(GMPPA):​c.210delA​(p.Ala71ProfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,452 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GMPPA NM_013335.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.89
• 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 18 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 2-219501545-GA-G is Pathogenic according to our data. Variant chr2-219501545-GA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 88694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.210delA	p.Ala71ProfsTer19	frameshift	Exon 4 of 13	NP_037467.2
	GMPPA	NM_001438893.1		c.210delA	p.Ala71ProfsTer19	frameshift	Exon 4 of 12	NP_001425822.1
	GMPPA	NM_001438894.1		c.210delA	p.Ala71ProfsTer19	frameshift	Exon 4 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.210delA	p.Ala71ProfsTer19	frameshift	Exon 4 of 13	ENSP00000315925.6	Q96IJ6-1
	GMPPA	ENST00000358215.8	TSL:1	c.210delA	p.Ala71ProfsTer19	frameshift	Exon 4 of 13	ENSP00000350949.3	Q96IJ6-1
	GMPPA	ENST00000950500.1		c.210delA	p.Ala71ProfsTer19	frameshift	Exon 4 of 13	ENSP00000620559.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460452 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726656

African (AFR) AF: 0.0000299 AC: 1 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110714

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Alacrima, achalasia, and intellectual disability syndrome (1)
1	-	-	Chromosomal instability with tissue-specific radiosensitivity (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886037654; hg19: chr2-220366267;