rs1057519338
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_015365.3(AMMECR1):c.502C>T(p.Arg168Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 23)
Consequence
AMMECR1
NM_015365.3 stop_gained
NM_015365.3 stop_gained
Scores
2
2
1
Clinical Significance
Conservation
PhyloP100: 7.68
Genes affected
AMMECR1 (HGNC:467): (AMMECR nuclear protein 1) The exact function of this gene is not known, however, submicroscopic deletion of the X chromosome including this gene, COL4A5, and FACL4 genes, result in a contiguous gene deletion syndrome, the AMME complex (Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 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;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AMMECR1 | NM_015365.3 | c.502C>T | p.Arg168Ter | stop_gained | 2/6 | ENST00000262844.10 | |
AMMECR1 | NM_001171689.2 | c.133C>T | p.Arg45Ter | stop_gained | 4/8 | ||
AMMECR1 | NM_001025580.2 | c.474-47939C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AMMECR1 | ENST00000262844.10 | c.502C>T | p.Arg168Ter | stop_gained | 2/6 | 1 | NM_015365.3 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 27
GnomAD4 exome
Cov.:
27
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis Pathogenic:2
Pathogenic, no assertion criteria provided | research | Genetics Division, Universidade Federal de Sao Paulo | - | The patient with this variant has AMMECR1 loss of function and overlapping phenotypes with the patients described in Basel-Vanagaite et al. 2017 (PMID: 28089922) and Andreoletti et al. 2017 (PMID: 27811305). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 25, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 02, 2021 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Studies have shown that this variant is associated with skipping of exon 2 but is expected to preserve the integrity of the reading frame (PMID: 28089922). This variant has been observed in individual(s) with clinical features of AMMECR1-related conditions (PMID: 29193635, 28089922). This variant is also known as p.Arg45*. ClinVar contains an entry for this variant (Variation ID: 375305). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg168*) in the AMMECR1 gene. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at