19-48965340-G-C

Position:

• chr19-48965340-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_000146.4(FTL):​c.-168G>C variant causes a 5 prime UTR change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FTL NM_000146.4 5_prime_UTR
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.53

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-48965340-G-C is Pathogenic according to our data. Variant chr19-48965340-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.14). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FTL	NM_000146.4	c.-168G>C		5_prime_UTR_variant	1/4	ENST00000331825.11	NP_000137.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FTL	ENST00000331825	c.-168G>C		5_prime_UTR_variant	1/4	1	NM_000146.4	ENSP00000366525.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 518068 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 279588

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary hyperferritinemia with congenital cataracts Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 19, 2013

- -

Hereditary hyperferritinemia with congenital cataracts;C1853578:Neuroferritinopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 29, 2021

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 16485). This variant is also known as 32G>C or G32C. This variant has been observed in individuals with hyperferritinemia-cataract syndrome (PMID: 12200611, 14662596, 21541272). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). 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. -

FTL-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2024

The FTL c.-168G>C variant is located in the 5' untranslated region. This variant is alternatively referred to as 32G>C, G32C, or Baltimore-1 in the literature. It has been reported in many individuals with hyperferritinemia-cataract syndrome and shown to segregate with disease in multiple families (see, for example, Campagnoli et al 2002. PubMed ID: 12200611; Craig et al 2003. PubMed ID: 14662596; Ferro et al. 2018. PubMed ID: 29426274). 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 this position (c.-168G>A, c.-168G>T), have also been found in patients with FTL-related disorders (Cazzola et al.1997. PubMed ID: 9226182; Martin et al. 1998. PubMed ID: 9414300). This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 12, 2024

No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 14662596, 29426274, 21936912, 21541272, 12200611, 33221470, 23421845, 37745687, Collantes2023[abstract]) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Benign	0.94

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: rs398124635; hg19: chr19-49468597;