chr1-212858455-G-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_014053.4(FLVCR1):c.3G>T(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,437,798 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 (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
FLVCR1
NM_014053.4 start_lost
NM_014053.4 start_lost
Scores
5
4
7
Clinical Significance
Conservation
PhyloP100: 0.642
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 Pathogenic. Variant got 20 ACMG points.
PVS1
Start lost variant, next in-frame start position is after 11 pathogenic variants. Next in-frame start position is after 450 CDS bases. Genomic position: 212858902. Lost 0.270 part of the original CDS.
PS1
Another start lost variant in NM_014053.4 (FLVCR1) was described as [Likely_pathogenic] in ClinVar as 521372
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-212858455-G-T is Pathogenic according to our data. Variant chr1-212858455-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 521373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.0000109 AC: 14AN: 1285628Hom.: 0 Cov.: 31 AF XY: 0.00000961 AC XY: 6AN XY: 624060
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74336
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 13, 2016 | - - |
Posterior column ataxia-retinitis pigmentosa syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 21, 2025 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 01, 2022 | ClinVar contains an entry for this variant (Variation ID: 521373). This variant disrupts the p.Asn121 amino acid residue in FLVCR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21070897, 22483575, 28559085). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Disruption of the initiator codon has been observed in individual(s) with sensory and autonomic neuropathy (PMID: 31408049). It has also been observed to segregate with disease in related individuals. This sequence change affects the initiator methionine of the FLVCR1 mRNA. The next in-frame methionine is located at codon 151. This variant is not present in population databases (gnomAD no frequency). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
B
Vest4
MutPred
Loss of helix (P = 0.1706);
MVP
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