rs139732572

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5

The NM_000146.4(FTL):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,612,424 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

FTL
NM_000146.4 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 8.51

Variant links:

Genes affected

FTL (HGNC:3999): (ferritin light chain) This gene encodes the light subunit of the ferritin protein. Ferritin is the major intracellular iron storage protein in prokaryotes and eukaryotes. It is composed of 24 subunits of the heavy and light ferritin chains. Variation in ferritin subunit composition may affect the rates of iron uptake and release in different tissues. A major function of ferritin is the storage of iron in a soluble and nontoxic state. Defects in this light chain ferritin gene are associated with several neurodegenerative diseases and hyperferritinemia-cataract syndrome. This gene has multiple pseudogenes. [provided by RefSeq, Jul 2008]

FTL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PP5

Variant 19-48965508-A-G is Pathogenic according to our data. Variant chr19-48965508-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96689.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}. Variant chr19-48965508-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FTL	NM_000146.4 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/4	ENST00000331825.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FTL	ENST00000331825.11 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/4	1	NM_000146.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251104

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135766

show subpopulations

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1460284

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726578

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000280

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

L-ferritin deficiency

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 12, 2022	Variant summary: FTL c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (Met69) is located in the encoded protein. An activation of this potential downstream translation initiation site would result in a shortened protein missing the first 68 amino acids from the protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The variant allele was found at a frequency of 1.2e-05 in 251104 control chromosomes (gnomAD). c.1A>G has been reported in the literature in at least two heterozygous individuals affected with autosomal dominant L-Ferritin Deficiency (e.g. Cremonesi_2004, Cadenas_2019). These data indicate that the variant may be associated with disease. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 25, 2023	The heterozygous p.Met1Val variant in FTL was identified by our study in one individual with low serum ferritin. The p.Met1Val variant in FTL has been reported in 2 unrelated individuals with autosomal dominant L-ferritin deficiency (PMID: 30678075, PMID: 15173247) and segregated with disease in 2 affective relatives from one family (PMID: 30678075), but has been identified in 0.003% (3/113706) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs139732572). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Pathogenic variants may be present at a low frequency in the general population, for diseases with clinical variability, or reduced penetrance. This variant has also been reported in ClinVar (Variation ID: 96689) and has been interpreted as pathogenic by OMIM, as likely pathogenic by LabCorp, and as a variant of uncertain significance by Invitae. This variant is located in the first amino acid and obliterates the methionine initiation codon. The next in-frame methionine is at amino acid residue 69 and there are 2 reported pathogenic or likely pathogenic variants in ClinVar upstream of this downstream methionine. It is of note that loss of function of FTL in an autosomal dominant disease has not yet been established based on the criteria laid out in Tayoun et al., 2018 (PMID: 30192042). In summary, the clinical significance of the p.Met1Val variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting (Richards 2015). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2004	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

FTL: PM2, PS4:Moderate, PVS1:Moderate, PP1, PP4 -

Hereditary hyperferritinemia with congenital cataracts;C1853578:Neuroferritinopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 02, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 96689). Disruption of the initiator codon has been observed in individual(s) with L-ferritin deficiency (PMID: 15173247, 30678075). This variant is present in population databases (rs139732572, gnomAD 0.003%). This sequence change affects the initiator methionine of the FTL mRNA. The next in-frame methionine is located at codon 69. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.28

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.55

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.87

MetaSVM

Benign

-0.58

MutationTaster

Benign

1.0

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.54

Sift

Uncertain

0.015

Sift4G

Uncertain

0.053

Polyphen

0.11

Vest4

0.93

MVP

0.70

ClinPred

0.90

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.40

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over