rs1060501102

Positions:

• chr2-189562125-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_014585.6(SLC40A1):​c.1469G>A​(p.Gly490Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC40A1 NM_014585.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 2-189562125-C-T is Pathogenic according to our data. Variant chr2-189562125-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 406376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC40A1	NM_014585.6	c.1469G>A	p.Gly490Asp	missense_variant	8/8	ENST00000261024.7	NP_055400.1
SLC40A1	XM_047444066.1	c.1349G>A	p.Gly450Asp	missense_variant	8/8		XP_047300022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC40A1	ENST00000261024.7	c.1469G>A	p.Gly490Asp	missense_variant	8/8	1	NM_014585.6	ENSP00000261024.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hemochromatosis type 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Molecular Genetics and Genomics, Rennes University Hospital	Jul 01, 2020	Identified in 11 patients harbouring clinical and biochemical symptomes of type 4 haemochromatosis -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 12, 2022	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 490 of the SLC40A1 protein (p.Gly490Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hyperferritinemia and iron overload (PMID: 12873829, 21199650, 24714983). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 406376). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects SLC40A1 function (PMID: 15692071, 15956209, 24714983). For these reasons, this variant has been classified as Pathogenic. -

SLC40A1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2024

The SLC40A1 c.1469G>A variant is predicted to result in the amino acid substitution p.Gly490Asp. This variant was reported in patients with hemochromatosis type 4 (Jouanelle et al. 2003. PubMed ID: 12873829; Rice et al. 2009. PubMed ID: 19150361; Le Gac et al. 2013. PubMed ID: 23784628; Callebaut et al. 2014. PubMed ID: 24714983). An in vitro study showed that this variant caused a loss of iron export function (Schimanski et al. 2005. PubMed ID: 15692071). Of note, another missense variant affecting the same amino acid (p.Gly490Ser) has also been reported as causative for hyperferritinemia (Callebaut et al. 2014. PubMed ID: 24714983). This variant has not been reported in a large population database, indicating this variant is rare. This variant is classified as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/406376/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.5	M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.91		Gain of helix (P = 0.0199);
MVP		0.95
MPC		1.6
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.94
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1060501102; hg19: chr2-190426851; COSMIC: COSV53721695; COSMIC: COSV53721695;