19-48965347-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_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
Consequence
NM_000146.4 5_prime_UTR
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FTL | NM_000146.4 | c.-161C>T | 5_prime_UTR_variant | Exon 1 of 4 | ENST00000331825.11 | NP_000137.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000189 AC: 1AN: 528044Hom.: 0 Cov.: 4 AF XY: 0.00000350 AC XY: 1AN XY: 285550
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary hyperferritinemia with congenital cataracts Pathogenic:2
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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
FTL: PS2, PM2, PS4:Moderate, PP4, PS3:Supporting -
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Hereditary hyperferritinemia with congenital cataracts;C1853578:Neuroferritinopathy Pathogenic:1
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. 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). -
Hereditary hyperferritinemia with congenital cataracts;C1853578:Neuroferritinopathy;C3810090:L-ferritin deficiency Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at