rs752932113
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_016729.3(FOLR1):c.726G>A(p.Trp242Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,878 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
FOLR1
NM_016729.3 stop_gained
NM_016729.3 stop_gained
Scores
2
5
Clinical Significance
Conservation
PhyloP100: -1.13
Genes affected
FOLR1 (HGNC:3791): (folate receptor alpha) The protein encoded by this gene is a member of the folate receptor family. Members of this gene family bind folic acid and its reduced derivatives, and transport 5-methyltetrahydrofolate into cells. This gene product is a secreted protein that either anchors to membranes via a glycosyl-phosphatidylinositol linkage or exists in a soluble form. Mutations in this gene have been associated with neurodegeneration due to cerebral folate transport deficiency. Due to the presence of two promoters, multiple transcription start sites, and alternative splicing, multiple transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 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 0.062 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FOLR1 | NM_016729.3 | c.726G>A | p.Trp242Ter | stop_gained | 4/4 | ENST00000393676.5 | |
FOLR1 | NM_000802.3 | c.726G>A | p.Trp242Ter | stop_gained | 5/5 | ||
FOLR1 | NM_016724.3 | c.726G>A | p.Trp242Ter | stop_gained | 6/6 | ||
FOLR1 | NM_016725.3 | c.726G>A | p.Trp242Ter | stop_gained | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FOLR1 | ENST00000393676.5 | c.726G>A | p.Trp242Ter | stop_gained | 4/4 | 1 | NM_016729.3 | P1 | |
ENST00000378140.3 | n.419+2384C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251312Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135828
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GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461878Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14AN XY: 727238
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cerebral folate transport deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 19, 2022 | This sequence change creates a premature translational stop signal (p.Trp242*) in the FOLR1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the FOLR1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with seizures, motor deficits, speech defects, and abnormal EEG (Invitae). ClinVar contains an entry for this variant (Variation ID: 470727). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
D;D;D;D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at