rs267606819

Variant names:

• chr1-212859173-G-A
• rs267606819
• NM_014053.4:c.721G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_014053.4(FLVCR1):​c.721G>A​(p.Ala241Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,736 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A241V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FLVCR1 NM_014053.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.50
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• FLVCR1-related retinopathy with or without ataxia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• posterior column ataxia-retinitis pigmentosa syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856
• PP5: Variant 1-212859173-G-A is Pathogenic according to our data. Variant chr1-212859173-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 18419.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLVCR1	NM_014053.4	c.721G>A	p.Ala241Thr	missense_variant	Exon 1 of 10	ENST00000366971.9	NP_054772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLVCR1	ENST00000366971.9	c.721G>A	p.Ala241Thr	missense_variant	Exon 1 of 10	1	NM_014053.4	ENSP00000355938.4
FLVCR1	ENST00000419102.1	c.256G>A	p.Ala86Thr	missense_variant	Exon 1 of 9	5		ENSP00000414680.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461736 Hom.: 0 Cov.: 62 AF XY: 0.00000275 AC XY: 2 AN XY: 727158

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Posterior column ataxia-retinitis pigmentosa syndrome Pathogenic:1

Nov 12, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Feb 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies have shown that this missense change affects FLVCR1 function (PMID: 22483575). ClinVar contains an entry for this variant (Variation ID: 18419). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with FLVCR1-related conditions (PMID: 21070897). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 241 of the FLVCR1 protein (p.Ala241Thr). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.85
Sift	Benign	0.047	D
Sift4G	Uncertain	0.041	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.61		Gain of glycosylation at A241 (P = 0.058);
MVP		1.0
MPC		1.8
ClinPred		0.99	D
GERP RS		5.2
PromoterAI		-0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.65
gMVP		0.61
Mutation Taster		=22/78	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267606819; hg19: chr1-213032515;