chr1-212858454-T-C

Position:

• chr1-212858454-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014053.4(FLVCR1):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000156 in 1,283,410 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: FLVCR1 NM_014053.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.51

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-212858454-T-C is Pathogenic according to our data. Variant chr1-212858454-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLVCR1	NM_014053.4	c.2T>C	p.Met1?	start_lost	1/10	ENST00000366971.9	NP_054772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLVCR1	ENST00000366971.9	c.2T>C	p.Met1?	start_lost	1/10	1	NM_014053.4	ENSP00000355938	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000370 AC: 2 AN: 54006 Hom.: 0 AF XY: 0.0000364 AC XY: 1 AN XY: 27440

Gnomad AFR exome AF: 0.00

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: 0.0000982

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000156 AC: 2 AN: 1283410 Hom.: 0 Cov.: 31 AF XY: 0.00000161 AC XY: 1 AN XY: 622752

Gnomad4 AFR exome AF: 0.00

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: 0.00000194

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2023	Published functional studies demonstrate a damaging effect on protein function (PMID: 31408049); This variant is associated with the following publications: (PMID: 32822874, 21070897, 9409377, 27923065, 24628582, 22279524, 21267618, 31964843, 31408049) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 04, 2022	Disruption of the initiator codon has been observed in individuals with FLVCR1-related conditions (PMID: 31408049, 32822874). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of the initiator codon alters FLVCR1 gene expression (PMID: 31408049). ClinVar contains an entry for this variant (Variation ID: 521372). This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change affects the initiator methionine of the FLVCR1 mRNA. The next in-frame methionine is located at codon 151. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2016

- -

Posterior column ataxia-retinitis pigmentosa syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Ocular Genomics Institute, Massachusetts Eye and Ear

Apr 08, 2021

The FLVCR1 c.2T>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2. Based on this evidence we have classified this variant as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.35	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.037	B
Vest4		0.62
MutPred		0.99		Gain of glycosylation at M1 (P = 7e-04);
MVP		0.96
ClinPred		0.84	D
GERP RS		4.6
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9
Varity_R		0.83
gMVP		0.34

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: rs1468358104; hg19: chr1-213031796;