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rs878854984

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM2PP5_Very_StrongBP3

The NM_014585.6(SLC40A1):​c.485_487del​(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 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC40A1
NM_014585.6 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.11
Variant links:
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
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
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
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
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
?
    BP3 - In-frame deletions/insertions in a repetitive region without a known function
Nonframeshift variant in repetitive region in NM_014585.6

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC40A1NM_014585.6 linkuse as main transcriptc.485_487del p.Val162del inframe_deletion 5/8 ENST00000261024.7
SLC40A1XM_047444066.1 linkuse as main transcriptc.365_367del p.Val122del inframe_deletion 5/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC40A1ENST00000261024.7 linkuse as main transcriptc.485_487del p.Val162del inframe_deletion 5/81 NM_014585.6 P1
SLC40A1ENST00000427241.5 linkuse as main transcriptc.485_487del p.Val162del inframe_deletion 7/85

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460476
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
726654
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
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 submitterclinical testingInvitaeDec 01, 2023This 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 providedliterature onlyOMIMNov 01, 2002- -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory of Molecular Genetics and Genomics, Rennes University HospitalJul 01, 2020- -
SLC40A1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesDec 07, 2022The 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs878854984; hg19: chr2-190436467; API