rs398124636

Variant names:

• chr19-48965347-C-G
• rs398124636
• NM_000146.4:c.-161C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-48965347-C-G
• chr19-48965347-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000146.4(FTL):​c.-161C>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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FTL NM_000146.4 5_prime_UTR
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.78
• Publications: 2 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-48965347-C-G is Pathogenic according to our data. Variant chr19-48965347-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1321316.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.09). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTL	NM_000146.4	c.-161C>G		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.-161C>G		5_prime_UTR_variant	Exon 1 of 4	1	NM_000146.4	ENSP00000366525.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 4

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary hyperferritinemia with congenital cataracts Pathogenic:1

Nov 12, 2021

Genesis Genoma Lab, Genesis Genoma Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This sequence change falls in the non-coding 5'UTR , Iron Responsive Element (IRE) loop of the FTL gene. Nucleotide alterations in the IRE loop abrogate IPR binding and subsequently deregulate FTL synthesis. This sequence change is located in the non-coding 5'UTR of the FTL gene, where a significant number of previously reported variants are found to associate with hyperferritinemia (PMID: 19800271, 7493028, 23421845, 10383191, 22881709, 9226182). This variant has been observed in individuals and families affected with hyperferritinemia and cataract syndrome (PMID: 15234655, 16406710). This variant is also known as Paris +39C>G in the literature. It was detected in a girl with hyperferritinaemia and signs of catarract. For these reasons, this variant has been classified as Pathogenic -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Benign	0.94
PhyloP100		5.8
PromoterAI		-0.069	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=3/297	disease causing

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: rs398124636; hg19: chr19-49468604;