rs750609759
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003227.4(TFR2):c.1606-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000725 in 1,613,868 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_003227.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TFR2 | NM_003227.4 | c.1606-2A>G | splice_acceptor_variant, intron_variant | Intron 13 of 17 | ENST00000223051.8 | NP_003218.2 | ||
TFR2 | NM_001206855.3 | c.1093-2A>G | splice_acceptor_variant, intron_variant | Intron 10 of 14 | NP_001193784.1 | |||
LOC124901709 | XR_007060454.1 | n.434-3334T>C | intron_variant | Intron 1 of 2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151994Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251464Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135908
GnomAD4 exome AF: 0.0000794 AC: 116AN: 1461874Hom.: 1 Cov.: 41 AF XY: 0.0000743 AC XY: 54AN XY: 727248
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151994Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74234
ClinVar
Submissions by phenotype
Hemochromatosis type 3 Pathogenic:1
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Hereditary hemochromatosis Pathogenic:1
This sequence change affects an acceptor splice site in intron 13 of the TFR2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TFR2 are known to be pathogenic (PMID: 23600741, 26029709). This variant is present in population databases (rs750609759, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with type 3 hereditary haemochromatosis (PMID: 28276324). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 570407). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at