NM_013335.4:c.592T>C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_013335.4(GMPPA):โc.592T>Cโ(p.Phe198Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_013335.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GMPPA | NM_013335.4 | c.592T>C | p.Phe198Leu | missense_variant | Exon 7 of 13 | ENST00000313597.10 | NP_037467.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000131 AC: 33AN: 251434Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135890
GnomAD4 exome AF: 0.0000479 AC: 70AN: 1461814Hom.: 0 Cov.: 31 AF XY: 0.0000591 AC XY: 43AN XY: 727220
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74342
ClinVar
Submissions by phenotype
Alacrima, achalasia, and intellectual disability syndrome Uncertain:2Benign:1
The missense variant c.592T>C (p.Phe198Leu) in GMPPA has been submitted to ClinVar as Variant of Uncertain Significance (VUS). The p.Phe198Leu variant has allele frequency of 0.013% in the gnomad and novel (not in any individuals) in 1000 genome database. The amino acid Phe at position 198 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Phe198Leu in GMPPA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance (VUS). -
This sequence change replaces phenylalanine with leucine at codon 198 of the GMPPA protein (p.Phe198Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs773715630, ExAC 0.1%) but has not been reported in the literature in individuals with a GMPPA-related disease. In summary, this variant is a rare missense change with uncertain impact on protein function. ยฌโ There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). -
The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant. -
Inborn genetic diseases Uncertain:1
The c.592T>C (p.F198L) alteration is located in exon 7 (coding exon 6) of the GMPPA gene. This alteration results from a T to C substitution at nucleotide position 592, causing the phenylalanine (F) at amino acid position 198 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at