rs786204108
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_003227.4(TFR2):āc.2033G>Cā(p.Arg678Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000086 in 1,395,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Synonymous variant affecting the same amino acid position (i.e. R678R) has been classified as Likely benign.
Frequency
Consequence
NM_003227.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TFR2 | NM_003227.4 | c.2033G>C | p.Arg678Pro | missense_variant | 17/18 | ENST00000223051.8 | |
LOC124901709 | XR_007060454.1 | n.434-4290C>G | intron_variant, non_coding_transcript_variant | ||||
TFR2 | NM_001206855.3 | c.1520G>C | p.Arg507Pro | missense_variant | 14/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TFR2 | ENST00000223051.8 | c.2033G>C | p.Arg678Pro | missense_variant | 17/18 | 1 | NM_003227.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000860 AC: 12AN: 1395402Hom.: 0 Cov.: 36 AF XY: 0.00000581 AC XY: 4AN XY: 688520
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hemochromatosis type 3 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 14, 2024 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 06, 2020 | - - |
Hereditary hemochromatosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2021 | This sequence change replaces arginine with proline at codon 678 of the TFR2 protein (p.Arg678Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with hereditary hemochromatosis (PMID: 23600741, 26408288). ClinVar contains an entry for this variant (Variation ID: 188153). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at