7-100106278-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004722.4(AP4M1):c.1012C>T(p.Arg338Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004722.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AP4M1 | NM_004722.4 | c.1012C>T | p.Arg338Ter | stop_gained | 13/15 | ENST00000359593.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP4M1 | ENST00000359593.9 | c.1012C>T | p.Arg338Ter | stop_gained | 13/15 | 1 | NM_004722.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251138Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135804
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461778Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13AN XY: 727190
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74330
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 50 Pathogenic:5
Likely pathogenic, no assertion criteria provided | clinical testing | Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles | Jan 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000209980 / PMID: 24700674). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, CHRU Nancy | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2022 | ClinVar contains an entry for this variant (Variation ID: 209980). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individuals with spastic paraplegia (PMID: 24700674, 28464862). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs146262009, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Arg338*) in the AP4M1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AP4M1 are known to be pathogenic (PMID: 24700674, 25496299, 25558065). - |
Spastic paraplegia Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Oct 01, 2020 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 02, 2022 | Nonsense 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; This variant is associated with the following publications: (PMID: 31589614, 34402213, 25496299, 24700674, 25558065, 32979048, 28464862) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at