chr1-212858455-G-T

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

Scores

5
4
7

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 0.642
Variant links:
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]

Genome browser will be placed here

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

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FLVCR1NM_014053.4 linkc.3G>T p.Met1? start_lost Exon 1 of 10 ENST00000366971.9 NP_054772.1 Q9Y5Y0-1B2RB38

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLVCR1ENST00000366971.9 linkc.3G>T p.Met1? start_lost Exon 1 of 10 1 NM_014053.4 ENSP00000355938.4 Q9Y5Y0-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152170
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000109
AC:
14
AN:
1285628
Hom.:
0
Cov.:
31
AF XY:
0.00000961
AC XY:
6
AN XY:
624060
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000135
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152170
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000113

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 submitterclinical testingAmbry GeneticsDec 13, 2016- -
Posterior column ataxia-retinitis pigmentosa syndrome Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 21, 2025- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 01, 2022ClinVar 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Uncertain
0.050
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.12
T
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.039
FATHMM_MKL
Benign
0.64
D
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
0.98
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Benign
-0.34
T
PROVEAN
Benign
-0.19
N
REVEL
Uncertain
0.50
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.0080
B
Vest4
0.63
MutPred
1.0
Loss of helix (P = 0.1706);
MVP
0.96
ClinPred
1.0
D
GERP RS
3.9
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.9
Varity_R
0.87
gMVP
0.30

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs899735028; hg19: chr1-213031797; API