1-212858478-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014053.4(FLVCR1):c.26G>A(p.Gly9Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G9R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLVCR1 NM_014053.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.403

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.101970464).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLVCR1	NM_014053.4	c.26G>A	p.Gly9Glu	missense_variant	1/10	ENST00000366971.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLVCR1	ENST00000366971.9	c.26G>A	p.Gly9Glu	missense_variant	1/10	1	NM_014053.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 24, 2019

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with FLVCR1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces glycine with glutamic acid at codon 9 of the FLVCR1 protein (p.Gly9Glu). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	17
Dann	Benign	0.96
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.12
Sift	Benign	0.17	T
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.24		Gain of solvent accessibility (P = 0.0411);
MVP		0.80
MPC		1.2
ClinPred		0.11	T
GERP RS		2.1
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.4
Varity_R		0.042
gMVP		0.38

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

Other links and lift over

dbSNP: rs1664091368; hg19: chr1-213031820;