rs878854984
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM2PP5_Very_StrongBP3
The NM_014585.6(SLC40A1):βc.485_487delβ(p.Val162del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,476 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: not found (cov: 32)
Exomes π: 6.8e-7 ( 0 hom. )
Consequence
SLC40A1
NM_014585.6 inframe_deletion
NM_014585.6 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.11
Genes affected
SLC40A1 (HGNC:10909): (solute carrier family 40 member 1) The protein encoded by this gene is a cell membrane protein that may be involved in iron export from duodenal epithelial cells. Defects in this gene are a cause of hemochromatosis type 4 (HFE4). [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_014585.6
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-189571741-GCAA-G is Pathogenic according to our data. Variant chr2-189571741-GCAA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP3
?
Nonframeshift variant in repetitive region in NM_014585.6
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC40A1 | NM_014585.6 | c.485_487del | p.Val162del | inframe_deletion | 5/8 | ENST00000261024.7 | |
SLC40A1 | XM_047444066.1 | c.365_367del | p.Val122del | inframe_deletion | 5/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC40A1 | ENST00000261024.7 | c.485_487del | p.Val162del | inframe_deletion | 5/8 | 1 | NM_014585.6 | P1 | |
SLC40A1 | ENST00000427241.5 | c.485_487del | p.Val162del | inframe_deletion | 7/8 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460476Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 726654
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hemochromatosis type 4 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This variant, c.485_487del, results in the deletion of 1 amino acid(s) of the SLC40A1 protein (p.Val162del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hereditary hemochromatosis (PMID: 12091366, 24714983, 29154924, 31689754). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5414). 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 SLC40A1 function (PMID: 15692071, 16440176, 24714983). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2002 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics and Genomics, Rennes University Hospital | Jul 01, 2020 | - - |
SLC40A1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 07, 2022 | The SLC40A1 c.485_487delTTG variant is predicted to result in an in-frame deletion (p.Val162del). This variant has previously been reported to be causative for hemochromatosis, type 4 (Wallace et al 2002. PubMed ID: 12091366; Devalia V et al 2002. PubMed ID: 12091367; Callebaut I et al 2014. PubMed ID: 24714983). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at