19-48965347-C-T

Position:

• chr19-48965347-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000146.4(FTL):​c.-161C>T variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00000189 in 528,044 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: FTL NM_000146.4 5_prime_UTR
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.78

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-48965347-C-T is Pathogenic according to our data. Variant chr19-48965347-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48965347-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FTL	NM_000146.4	c.-161C>T		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	ENST00000331825.11	c.-161C>T		5_prime_UTR_variant	1/4	1	NM_000146.4	ENSP00000366525	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000189 AC: 1 AN: 528044 Hom.: 0 Cov.: 4 AF XY: 0.00000350 AC XY: 1 AN XY: 285550

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: 0.00000329

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary hyperferritinemia with congenital cataracts Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 19, 2013	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The heterozygous c.-161C>T variant in FTL was identified by our study in one individual with hyperferritinemia. The c.-161C>T variant in FTL has been previously reported in three individuals with hereditary hyperferritinemia with congenital cataracts (PMID: 10366790, PMID: 9414313, PMID: 10366804). This variant was found to be de novo in one individual with confirmed paternity and maternity (PMID: 10366804). This variant was absent from large population studies. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 16480) and has been interpreted as pathogenic by Invitae and OMIM. In vitro functional studies provide some evidence that the c.-161C>T variant may impact protein function (PMID: 8233801). However, these types of assays may not accurately represent biological function. Multiple variants in the same region as c.-161C>T variant have been reported in association with disease in the literature and the c.-161C>T variant is located in the iron-responsive element (IRE) domain of FTL, which is involved in regulating L-ferritin expression, suggesting suggesting that this variant is in a hot spot and key functional domain and slightly supports pathogenicity (PMID: 19800271, 7493028, 23421845, 10383191, 22881709, 9226182). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant hereditary hyperferritinemia with congenital cataracts. ACMG/AMP Criteria applied: PS2, PS3_Supporting, PS4_Supporting, PM1_Supporting, PM2_Supporting (Richards 2015). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	FTL: PS2, PM2, PS4:Moderate, PP4, PS3:Supporting -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 20, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects FTL function (PMID: 8233801). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 16480). This variant is also known as +39C>U, +39C>T. This variant has been observed in individual(s) with FTL-related conditions (PMID: 9414313, 10366790, 10366804; Invitae). In at least one individual the variant was observed to be de novo. 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. -

Hereditary hyperferritinemia with congenital cataracts;C1853578:Neuroferritinopathy;C3810090:L-ferritin deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
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

Other links and lift over

dbSNP: rs398124636; hg19: chr19-49468604;