NM_014053.4:c.28dupG

Variant names:

• chr1-212858475-A-AG
• rs992883082
• NM_014053.4:c.28dupG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_014053.4(FLVCR1):​c.28dupG​(p.Ala10GlyfsTer80) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000776 in 1,289,226 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A10A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: FLVCR1 NM_014053.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.725
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 57 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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.28dupG	p.Ala10GlyfsTer80	frameshift	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.28dupG	p.Ala10GlyfsTer80	frameshift	Exon 1 of 10	ENSP00000355938.4	Q9Y5Y0-1
	FLVCR1	ENST00000867613.1		c.28dupG	p.Ala10GlyfsTer80	frameshift	Exon 1 of 11	ENSP00000537672.1
	FLVCR1	ENST00000971333.1		c.28dupG	p.Ala10GlyfsTer80	frameshift	Exon 1 of 10	ENSP00000641392.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.76e-7 AC: 1 AN: 1289226 Hom.: 0 Cov.: 31 AF XY: 0.00000160 AC XY: 1 AN XY: 626032

⚠️ 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: 28078

American (AMR) AF: 0.00 AC: 0 AN: 20062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18904

East Asian (EAS) AF: 0.00 AC: 0 AN: 34704

South Asian (SAS) AF: 0.00 AC: 0 AN: 63392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3850

European-Non Finnish (NFE) AF: 9.67e-7 AC: 1 AN: 1034364

Other (OTH) AF: 0.00 AC: 0 AN: 53496

⚠️ 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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.72

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: rs992883082; hg19: chr1-213031817;