rs878854984

Positions:

• chr2-189571741-GCAA-G
• chr2-189571741-GCAA-GCAACAA

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP3

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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC40A1 NM_014585.6 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• 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	Protein	UniProt
SLC40A1	NM_014585.6	c.485_487del	p.Val162del	inframe_deletion	5/8	ENST00000261024.7	NP_055400.1
SLC40A1	XM_047444066.1	c.365_367del	p.Val122del	inframe_deletion	5/8		XP_047300022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC40A1	ENST00000261024.7	c.485_487del	p.Val162del	inframe_deletion	5/8	1	NM_014585.6	ENSP00000261024	P1
SLC40A1	ENST00000427241.5	c.485_487del	p.Val162del	inframe_deletion	7/8	5		ENSP00000390005

Frequencies

GnomAD3 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

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 Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hemochromatosis type 4 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Molecular Genetics and Genomics, Rennes University Hospital	Jul 01, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2002	- -

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

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs878854984; hg19: chr2-190436467;