19-48965340-G-C

Variant names:

• chr19-48965340-G-C
• rs398124635
• NM_000146.4:c.-168G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• hereditary hyperferritinemia with congenital cataracts

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• neuroferritinopathy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• L-ferritin deficiency

  Inheritance: Unknown, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• genetic hyperferritinemia without iron overload

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000305635 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.14).

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTL	ENST00000331825.11	c.-168G>C		5_prime_UTR_variant	Exon 1 of 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

African (AFR) AF: 0.00 AC: 0 AN: 14938

American (AMR) AF: 0.00 AC: 0 AN: 32904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18438

East Asian (EAS) AF: 0.00 AC: 0 AN: 30800

South Asian (SAS) AF: 0.00 AC: 0 AN: 60696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2274

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 297884

Other (OTH) AF: 0.00 AC: 0 AN: 28578

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

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

Dec 29, 2021

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: 12200611, 14662596, 21541272). It has also been observed to segregate with disease in related individuals. This variant is also known as 32G>C or G32C. ClinVar contains an entry for this variant (Variation ID: 16485). For these reasons, this variant has been classified as Pathogenic. -

FTL-related disorder Pathogenic:1

May 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Mar 12, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		9.5
PromoterAI		0.056	Neutral
Mutation Taster		=8/292	disease causing (ClinVar)

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: rs398124635; hg19: chr19-49468597;