rs144226457

Positions:

chr1-212895241-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014053.4(FLVCR1):c.1619A>G(p.Gln540Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,613,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

FLVCR1
NM_014053.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.811

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]

FLVCR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0167422).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FLVCR1	NM_014053.4 linkuse as main transcript	c.1619A>G	p.Gln540Arg	missense_variant	10/10	ENST00000366971.9	NP_054772.1
FLVCR1	XR_007059232.1 linkuse as main transcript	n.1686A>G		non_coding_transcript_exon_variant	9/10
FLVCR1	XR_247024.4 linkuse as main transcript	n.1797A>G		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLVCR1	ENST00000366971.9 linkuse as main transcript	c.1619A>G	p.Gln540Arg	missense_variant	10/10	1	NM_014053.4	ENSP00000355938	P1	Q9Y5Y0-1
FLVCR1	ENST00000419102.1 linkuse as main transcript	c.1016A>G	p.Gln339Arg	missense_variant	9/9	5		ENSP00000414680
FLVCR1	ENST00000483790.1 linkuse as main transcript	n.446A>G		non_coding_transcript_exon_variant	6/6	3

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251394

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00

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:

0.0000164

AC:

AN:

1461220

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726978

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000313

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:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000333

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 23, 2017

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The c.1619A>G (p.Q540R) alteration is located in exon 10 (coding exon 10) of the FLVCR1 gene. This alteration results from a A to G substitution at nucleotide position 1619, causing the glutamine (Q) at amino acid position 540 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 12, 2022

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 540 of the FLVCR1 protein (p.Gln540Arg). This variant is present in population databases (rs144226457, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with FLVCR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 447349). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.60

DEOGEN2

Benign

0.043

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.37

M_CAP

Benign

0.040

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.55

REVEL

Benign

0.21

Sift

Benign

0.21

Sift4G

Benign

0.23

Polyphen

0.0

Vest4

0.052

MVP

0.83

MPC

0.22

ClinPred

0.013

GERP RS

-0.070

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.026

gMVP

0.31

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over