rs139175550

chr1-212872731-G-Achr1-212872731-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014053.4(FLVCR1):c.937G>A(p.Asp313Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,613,774 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D313G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (16 hom.)
• Consequence: FLVCR1 NM_014053.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.00

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=0.0033223033).
• BP6: Variant 1-212872731-G-A is Benign according to our data. Variant chr1-212872731-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 447352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-212872731-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00235 (357/152094) while in subpopulation NFE AF= 0.00225 (153/68006). AF 95% confidence interval is 0.00196. There are 3 homozygotes in gnomad4. There are 228 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLVCR1	NM_014053.4	c.937G>A	p.Asp313Asn	missense_variant	3/10	ENST00000366971.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLVCR1	ENST00000366971.9	c.937G>A	p.Asp313Asn	missense_variant	3/10	1	NM_014053.4	P1
FLVCR1	ENST00000419102.1	c.420+8862G>A		intron_variant		5
FLVCR1	ENST00000474693.1	n.162G>A		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 357 AN: 151976 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00225

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00241 AC: 606 AN: 251296 Hom.: 4 AF XY: 0.00236 AC XY: 320 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0175

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00125 AC: 1826 AN: 1461680 Hom.: 16 Cov.: 30 AF XY: 0.00125 AC XY: 912 AN XY: 727168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0154

Gnomad4 NFE exome AF: 0.000828

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.00235 AC: 357 AN: 152094 Hom.: 3 Cov.: 32 AF XY: 0.00307 AC XY: 228 AN XY: 74352

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0187

Gnomad4 NFE AF: 0.00225

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00149 Hom.: 0

Bravo AF: 0.000642

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00222 AC: 270

EpiCase AF: 0.000491

EpiControl AF: 0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	FLVCR1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 09, 2018	- -

Posterior column ataxia-retinitis pigmentosa syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jul 20, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	15
Dann	Benign	0.92
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.050	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.13
Sift	Benign	0.50	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.19
MVP		0.31
MPC		0.20
ClinPred		0.015	T
GERP RS		-1.4
Varity_R		0.022
gMVP		0.30

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: rs139175550; hg19: chr1-213046073;