rs369434267
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_014053.4(FLVCR1):c.488C>T(p.Pro163Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,114 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: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
FLVCR1
NM_014053.4 missense
NM_014053.4 missense
Scores
4
13
2
Clinical Significance
Conservation
PhyloP100: 7.51
Genes affected
FLVCR1 (HGNC:24682): (FLVCR choline and heme transporter 1) This gene encodes a member of the major facilitator superfamily of transporter proteins. The encoded protein is a heme transporter that may play a critical role in erythropoiesis by protecting developing erythroid cells from heme toxicity. This gene may play a role in posterior column ataxia with retinitis pigmentosa and the hematological disorder Diamond-Blackfan syndrome. [provided by RefSeq, Jan 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.895
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLVCR1 | NM_014053.4 | c.488C>T | p.Pro163Leu | missense_variant | 1/10 | ENST00000366971.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLVCR1 | ENST00000366971.9 | c.488C>T | p.Pro163Leu | missense_variant | 1/10 | 1 | NM_014053.4 | P1 | |
FLVCR1 | ENST00000419102.1 | c.26C>T | p.Pro9Leu | missense_variant | 1/9 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152254Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 251044Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135714
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GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461860Hom.: 0 Cov.: 61 AF XY: 0.00000825 AC XY: 6AN XY: 727236
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152254Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74378
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 13, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 28, 2023 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FLVCR1 protein function. ClinVar contains an entry for this variant (Variation ID: 585880). This variant has not been reported in the literature in individuals affected with FLVCR1-related conditions. This variant is present in population databases (rs369434267, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 163 of the FLVCR1 protein (p.Pro163Leu). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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