rs398124633

Positions:

• chr19-48965348-A-G

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.-160A>G variant causes a 5 prime UTR change. 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FTL NM_000146.4 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.02

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 19-48965348-A-G is Pathogenic according to our data. Variant chr19-48965348-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 16474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48965348-A-G is described in Lovd as [Pathogenic].
• 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	UniProt
FTL	NM_000146.4	c.-160A>G		5_prime_UTR_variant	1/4	ENST00000331825.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FTL	ENST00000331825.11	c.-160A>G		5_prime_UTR_variant	1/4	1	NM_000146.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 4

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	FTL: PP1:Strong, PM2, PP4:Moderate, PS3:Moderate, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

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

Invitae

Jan 16, 2024

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 hereditary hyperferritinemia and cataract syndrome (PMID: 7493028, 11703332, 14662596, 24766965, 30401656). It has also been observed to segregate with disease in related individuals. This variant is also known as A40G. ClinVar contains an entry for this variant (Variation ID: 16474). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects FTL function (PMID: 7493028). For these reasons, this variant has been classified as Pathogenic. -

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: rs398124633; hg19: chr19-49468605;