Genetic Variant NM_013335.4:c.210delA (chr2-219501545-GA-G) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 2.89

Publications

0 publications found

Variant links:

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 links:

ASIC4-AS1 (HGNC:40960): (ASIC4 antisense RNA 1)

ASIC4-AS1 links:

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ACMG classification

Classification was made for transcript

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 id is 88694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMPPA	NM_013335.4 link	c.210delA	p.Ala71ProfsTer19	frameshift_variant	Exon 4 of 13	ENST00000313597.10	NP_037467.2	Q96IJ6-1A0A384MDS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMPPA	ENST00000313597.10 link	c.210delA	p.Ala71ProfsTer19	frameshift_variant	Exon 4 of 13	1	NM_013335.4	ENSP00000315925.6		Q96IJ6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460452

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726656

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110714

Other (OTH)

AF:

0.00

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alacrima, achalasia, and intellectual disability syndrome

Pathogenic:1

Oct 03, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Chromosomal instability with tissue-specific radiosensitivity

Pathogenic:1

Jan 22, 2020

New York Genome Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.210del, p.Ala71ProfsTer19 is a frameshift variant in GMPPA gene and has been reported in a patient with Alacrima, achalasia, and mental retardation syndrome [MIM#615510] [PMID: 24035193]. This variant is not reported in gnomAD database, indicating this is a rare allele. The detected variant causes a 1 bp deletion at amino acid 71, which is predicted to cause a frameshift and premature stop further downstream and in silico tool predicts the variant is expected to result in an absent protein product through nonsense-mediated mRNA decay [PMID: 24681721]. Based on the available evidence, the variant c.210del,p.Ala71ProfsTer19 in the GMPPA gene is classified as pathogenic. -

not provided

Pathogenic:1

Jan 24, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24035193) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.9

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over