rs80338888
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_Very_Strong
The NM_003227.4(TFR2):βc.1861_1872delβ(p.Ala621_Gln624del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000834 in 1,559,462 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. A621A) has been classified as Likely benign.
Frequency
Genomes: π 0.000020 ( 0 hom., cov: 33)
Exomes π: 0.0000071 ( 0 hom. )
Consequence
TFR2
NM_003227.4 inframe_deletion
NM_003227.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.17
Genes affected
TFR2 (HGNC:11762): (transferrin receptor 2) This gene encodes a single-pass type II membrane protein, which is a member of the transferrin receptor-like family. This protein mediates cellular uptake of transferrin-bound iron, and may be involved in iron metabolism, hepatocyte function and erythrocyte differentiation. Mutations in this gene have been associated with hereditary hemochromatosis type III. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, May 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_003227.4.
PP5
?
Variant 7-100627386-GCTGGGCCACGGC-G is Pathogenic according to our data. Variant chr7-100627386-GCTGGGCCACGGC-G is described in ClinVar as [Pathogenic]. Clinvar id is 21370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-100627386-GCTGGGCCACGGC-G is described in Lovd as [Pathogenic]. Variant chr7-100627386-GCTGGGCCACGGC-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TFR2 | NM_003227.4 | c.1861_1872del | p.Ala621_Gln624del | inframe_deletion | 16/18 | ENST00000223051.8 | |
LOC124901709 | XR_007060454.1 | n.434-3757_434-3746del | intron_variant, non_coding_transcript_variant | ||||
TFR2 | NM_001206855.3 | c.1348_1359del | p.Ala450_Gln453del | inframe_deletion | 13/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TFR2 | ENST00000223051.8 | c.1861_1872del | p.Ala621_Gln624del | inframe_deletion | 16/18 | 1 | NM_003227.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000711 AC: 10AN: 1407252Hom.: 0 AF XY: 0.00000576 AC XY: 4AN XY: 694998
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74338
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hemochromatosis type 3 Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 07, 2024 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Hereditary hemochromatosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This variant, c.1861_1872del, results in the deletion of 4 amino acid(s) of the TFR2 protein (p.Ala621_Gln624del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs80338888, gnomAD 0.004%). This variant has been observed in individuals with hereditary hemochromatosis (PMID: 11984516, 12809944, 26408288). It has also been observed to segregate with disease in related individuals. This variant is also known as AVAQ 594-597 del. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects TFR2 function (PMID: 18094142, 26408288). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at