1-212858501-C-T

Variant names:

• chr1-212858501-C-T
• rs543847452
• NM_014053.4:c.49C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014053.4(FLVCR1):​c.49C>T​(p.Pro17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000772 in 1,295,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. P17A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: FLVCR1 NM_014053.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.769
• Publications: 0 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-DT (HGNC:39077): (FLVCR1 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16616946).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014053.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLVCR1	NM_014053.4	MANE Select	c.49C>T	p.Pro17Ser	missense	Exon 1 of 10	NP_054772.1	Q9Y5Y0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLVCR1	ENST00000366971.9	TSL:1 MANE Select	c.49C>T	p.Pro17Ser	missense	Exon 1 of 10	ENSP00000355938.4	Q9Y5Y0-1
	FLVCR1	ENST00000867613.1		c.49C>T	p.Pro17Ser	missense	Exon 1 of 11	ENSP00000537672.1
	FLVCR1	ENST00000971333.1		c.49C>T	p.Pro17Ser	missense	Exon 1 of 10	ENSP00000641392.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.72e-7 AC: 1 AN: 1295132 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 629144

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28316

American (AMR) AF: 0.00 AC: 0 AN: 20812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19120

East Asian (EAS) AF: 0.00 AC: 0 AN: 34740

South Asian (SAS) AF: 0.00 AC: 0 AN: 63994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4150

European-Non Finnish (NFE) AF: 9.66e-7 AC: 1 AN: 1035658

Other (OTH) AF: 0.00 AC: 0 AN: 53692

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.77
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.097
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.032	D
Polyphen		0.0010	B
Vest4		0.093
MutPred		0.19		Loss of sheet (P = 0.0181)
MVP		0.95
MPC		1.0
ClinPred		0.089	T
GERP RS		3.0
PromoterAI		0.0099	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9
Varity_R		0.048
gMVP		0.47
Mutation Taster		=99/1	polymorphism

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: rs543847452; hg19: chr1-213031843;