rs398124637

Variant names:

• chr19-48965344-C-A
• rs398124637
• NM_000146.4:c.-164C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-48965344-C-A
• chr19-48965344-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000146.4(FTL):​c.-164C>A variant causes a 5 prime UTR change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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:3
• Conservation: PhyloP100: 7.55
• Publications: 5 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: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-48965344-C-A is Pathogenic according to our data. Variant chr19-48965344-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000146.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTL	NM_000146.4	MANE Select	c.-164C>A		5_prime_UTR	Exon 1 of 4	NP_000137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTL	ENST00000331825.11	TSL:1 MANE Select	c.-164C>A		5_prime_UTR	Exon 1 of 4	ENSP00000366525.2
	ENSG00000305635	ENST00000812089.1		n.404G>T		non_coding_transcript_exon	Exon 2 of 3
	ENSG00000305635	ENST00000812091.1		n.610G>T		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 525598 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 284060

African (AFR) AF: 0.00 AC: 0 AN: 15144

American (AMR) AF: 0.00 AC: 0 AN: 33474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18780

East Asian (EAS) AF: 0.00 AC: 0 AN: 31078

South Asian (SAS) AF: 0.00 AC: 0 AN: 61260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 302514

Other (OTH) AF: 0.00 AC: 0 AN: 28998

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary hyperferritinemia with congenital cataracts Pathogenic:2

Feb 19, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Sep 17, 2024

Clinical Genetics Laboratory, Region Ostergotland

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The following ACMG criteria were applied in classifying this variant: PM2, PP4, PM1, PP1supp

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

Oct 24, 2024

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 clinical features of hereditary hyperferritinemia-cataract syndrome (PMID: 9414313; internal data). It has also been observed to segregate with disease in related individuals. This variant is also known as +36C>A. ClinVar contains an entry for this variant (Variation ID: 16481). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant is located in a region of the FTL protein where a significant number of FTL frameshift mutations are have been reported in association with autosomal dominant neurodegeneration with brain iron accumulation (PMID: 36233161, 15099026, 11438811, 25832658). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Benign	0.97
PhyloP100		7.5
PromoterAI		0.042	Neutral
Mutation Taster		=11/289	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: rs398124637; hg19: chr19-49468601;