rs3207090

chr1-212895253-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014053.4(FLVCR1):c.1631C>T(p.Thr544Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 1,609,178 control chromosomes in the GnomAD database, including 180,923 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T544I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.40 (13343 hom., cov: 31)
  • Exomes 𝑓: 0.47 (167580 hom.)
• Consequence: FLVCR1 NM_014053.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.572

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.3459066E-5).
• BP6: Variant 1-212895253-C-T is Benign according to our data. Variant chr1-212895253-C-T is described in ClinVar as [Benign]. Clinvar id is 129103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-212895253-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLVCR1	NM_014053.4	c.1631C>T	p.Thr544Met	missense_variant	10/10	ENST00000366971.9
FLVCR1	XR_007059232.1	n.1698C>T		non_coding_transcript_exon_variant	9/10
FLVCR1	XR_247024.4	n.1809C>T		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLVCR1	ENST00000366971.9	c.1631C>T	p.Thr544Met	missense_variant	10/10	1	NM_014053.4	P1
FLVCR1	ENST00000419102.1	c.1028C>T	p.Thr343Met	missense_variant	9/9	5
FLVCR1	ENST00000483790.1	n.458C>T		non_coding_transcript_exon_variant	6/6	3

Frequencies

GnomAD3 genomes AF: 0.395 AC: 59958 AN: 151630 Hom.: 13346 Cov.: 31

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.574

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.391

GnomAD3 exomes AF: 0.443 AC: 111417 AN: 251248 Hom.: 26415 AF XY: 0.457 AC XY: 62041 AN XY: 135790

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.283

Gnomad ASJ exome AF: 0.375

Gnomad EAS exome AF: 0.478

Gnomad SAS exome AF: 0.498

Gnomad FIN exome AF: 0.571

Gnomad NFE exome AF: 0.491

Gnomad OTH exome AF: 0.433

GnomAD4 exome AF: 0.474 AC: 690842 AN: 1457430 Hom.: 167580 Cov.: 37 AF XY: 0.476 AC XY: 344913 AN XY: 725308

Gnomad4 AFR exome AF: 0.184

Gnomad4 AMR exome AF: 0.289

Gnomad4 ASJ exome AF: 0.377

Gnomad4 EAS exome AF: 0.474

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.567

Gnomad4 NFE exome AF: 0.488

Gnomad4 OTH exome AF: 0.445

GnomAD4 genome AF: 0.395 AC: 59953 AN: 151748 Hom.: 13343 Cov.: 31 AF XY: 0.401 AC XY: 29714 AN XY: 74114

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.377

Gnomad4 EAS AF: 0.476

Gnomad4 SAS AF: 0.520

Gnomad4 FIN AF: 0.574

Gnomad4 NFE AF: 0.490

Gnomad4 OTH AF: 0.388

Alfa AF: 0.463 Hom.: 42184

Bravo AF: 0.363

TwinsUK AF: 0.496 AC: 1839

ALSPAC AF: 0.492 AC: 1898

ESP6500AA AF: 0.209 AC: 920

ESP6500EA AF: 0.475 AC: 4086

ExAC AF: 0.449 AC: 54534

Asia WGS AF: 0.452 AC: 1573 AN: 3478

EpiCase AF: 0.475

EpiControl AF: 0.472

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Posterior column ataxia-retinitis pigmentosa syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 15, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	10
Dann	Benign	0.95
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.000023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.30	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.042	D
Polyphen		0.86	P
Vest4		0.036
MPC		0.30
ClinPred		0.0033	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.014
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3207090; hg19: chr1-213068595; COSMIC: COSV65323463;