chr14-75634956-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_017791.3(FLVCR2):​c.1067C>A​(p.Ala356Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,742 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: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

FLVCR2
NM_017791.3 missense

Scores

4
13
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.71
Variant links:
Genes affected
FLVCR2 (HGNC:20105): (FLVCR choline and putative heme transporter 2) This gene encodes a member of the major facilitator superfamily. The encoded transmembrane protein is a calcium transporter. Unlike the related protein feline leukemia virus subgroup C receptor 1, the protein encoded by this locus does not bind to feline leukemia virus subgroup C envelope protein. The encoded protein may play a role in development of brain vascular endothelial cells, as mutations at this locus have been associated with proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome. Alternatively spliced transcript variants have been described.[provided by RefSeq, Aug 2010]
TTLL5 (HGNC:19963): (tubulin tyrosine ligase like 5) This gene encodes a member of the tubulin tyrosine ligase like protein family. This protein interacts with two glucocorticoid receptor coactivators, transcriptional intermediary factor 2 and steroid receptor coactivator 1. This protein may function as a coregulator of glucocorticoid receptor mediated gene induction and repression. This protein may also function as an alpha tubulin polyglutamylase.[provided by RefSeq, Feb 2010]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FLVCR2NM_017791.3 linkuse as main transcriptc.1067C>A p.Ala356Glu missense_variant 5/10 ENST00000238667.9 NP_060261.2
FLVCR2NM_001195283.2 linkuse as main transcriptc.452C>A p.Ala151Glu missense_variant 5/10 NP_001182212.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FLVCR2ENST00000238667.9 linkuse as main transcriptc.1067C>A p.Ala356Glu missense_variant 5/101 NM_017791.3 ENSP00000238667 P1Q9UPI3-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251320
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135818
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000868
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461742
Hom.:
0
Cov.:
30
AF XY:
0.00000550
AC XY:
4
AN XY:
727186
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000112
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 01, 2024The c.1067C>A (p.A356E) alteration is located in exon 5 (coding exon 5) of the FLVCR2 gene. This alteration results from a C to A substitution at nucleotide position 1067, causing the alanine (A) at amino acid position 356 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 08, 2022In 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) performed at Invitae indicates that this missense variant is expected to disrupt FLVCR2 protein function. This variant has not been reported in the literature in individuals affected with FLVCR2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.009%). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 356 of the FLVCR2 protein (p.Ala356Glu). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Uncertain
0.068
T
BayesDel_noAF
Uncertain
0.060
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.66
D;.;.;.;T;T
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.97
D;D;D;D;D;D
M_CAP
Benign
0.039
D
MetaRNN
Pathogenic
0.76
D;D;D;D;D;D
MetaSVM
Uncertain
-0.012
T
MutationAssessor
Uncertain
2.6
M;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.54
T
PROVEAN
Uncertain
-4.1
D;D;D;D;D;D
REVEL
Uncertain
0.47
Sift
Uncertain
0.0020
D;D;D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D;D
Polyphen
0.97
D;.;.;.;.;.
Vest4
0.83
MutPred
0.70
Gain of catalytic residue at V354 (P = 0);.;.;.;.;.;
MVP
0.91
MPC
0.95
ClinPred
0.98
D
GERP RS
5.6
Varity_R
0.96
gMVP
0.96

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: rs1415947098; hg19: chr14-76101299; API