chr9-109137529-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_014334.4(FRRS1L):c.808C>T(p.Gln270Ter) 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
FRRS1L
NM_014334.4 stop_gained
NM_014334.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 9.60
Genes affected
FRRS1L (HGNC:1362): (ferric chelate reductase 1 like) This gene encodes a component of the outer-core of an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor protein in the brain. The encoded protein is thought to interact with inner-core components of the receptor, and play a role in the modulation of glutamate signaling. Mutations in this gene are associated with early infantile epileptic encephalopathy 37. [provided by RefSeq, Jul 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0839 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 9-109137529-G-A is Pathogenic according to our data. Variant chr9-109137529-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 218151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-109137529-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FRRS1L | NM_014334.4 | c.808C>T | p.Gln270Ter | stop_gained | 5/5 | ENST00000561981.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FRRS1L | ENST00000561981.5 | c.808C>T | p.Gln270Ter | stop_gained | 5/5 | 1 | NM_014334.4 | P1 | |
FRRS1L | ENST00000644747.1 | c.*426C>T | 3_prime_UTR_variant, NMD_transcript_variant | 4/4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 37 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 05, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 14, 2024 | - - |
Chorea;C0036572:Seizure;C1838578:Progressive encephalopathy Pathogenic:1
Pathogenic, no assertion criteria provided | research | Kruer lab, Phoenix Children's Hospital | Nov 11, 2015 | Leads to loss of protein by immunoblot; leads to impaired co-localization with GluR1 component of AMPA receptor by TIRF; loss of FRRS1L leads to attenuated AMPA currents by electrophysiology - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
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