Genetic Variant FTL:c.-168G>A (chr19-48965340-G-A) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_000146.4(FTL):c.-168G>A variant causes a 5 prime UTR change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

FTL
NM_000146.4 5_prime_UTR

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 9.53

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:

ENSG00000267898 (HGNC:):

ENSG00000267898 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-48965340-G-A is Pathogenic according to our data. Variant chr19-48965340-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48965340-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.1). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTL	NM_000146.4 link	c.-168G>A		5_prime_UTR_variant	Exon 1 of 4	ENST00000331825.11	NP_000137.2	P02792A0A384MDR3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTL	ENST00000331825 link	c.-168G>A		5_prime_UTR_variant	Exon 1 of 4	1	NM_000146.4	ENSP00000366525.2		P02792
ENSG00000267898	ENST00000599784.1 link	n.*182G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

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:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

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:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Aug 21, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with hyperferritinemia-cataract syndrome who also harbored a heterozygous variant in the HFE gene in published literature (PMID: 28746593); This variant is associated with the following publications: (PMID: 23421845, 30678075, 26147798, 21907119, 31211687, 11703332, 20624502, 17951290, 20578964, 9226182, 16518306, 28746593) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary hyperferritinemia with congenital cataracts

Pathogenic:1

Feb 19, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary hyperferritinemia with congenital cataracts;C1853578:Neuroferritinopathy

Pathogenic:1

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the FTL gene. It does not change the encoded amino acid sequence of the FTL protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hyperferritinemia-cataract syndrome (PMID: 9226182, 16518306, 28746593). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16476). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

FTL-related disorder

Pathogenic:1

Jul 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FTL c.-168G>A variant is located in the 5' untranslated region. This variant, also known in the literature as Pavia 1, +32, and G32A, has been reported in multiple families with elevated serum ferritin and cataract (Family 1, Cazzola et al. 1997. PubMed ID: 9226182; Girelli et al. 2001. PubMed ID: 11703332; Case 1, Petroni et al. 2017. PubMed ID: 28746593; Vanita et al. 2006. PubMed ID: 16518306; Family 1, Volkmann et al. 2019. PubMed ID: 31211687). This variant occurs within a highly conserved non-coding region known as the iron regulatory element and other variants within this region, including additional variants at the +32 position (G32T and G32C) have also been found in patients with FTL-related disorders (Cazzola et al. 1997. PubMed ID: 9226182; Girelli et al. 2001. PubMed ID: 11703332; Volkmann et al. 2019. PubMed ID: 31211687). This variant has not been reported in gnomAD, indicating this variant is rare. Based on this evidence, we interpret this variant pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Benign

0.97

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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