rs387907375

Positions:

• chr2-189571756-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The ENST00000261024.7(SLC40A1):​c.473G>T​(p.Trp158Leu) 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 Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W158C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC40A1 ENST00000261024.7 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:2 O:1
• Conservation: PhyloP100: 7.73

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 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000261024.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-189571755-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 568628.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC40A1	NM_014585.6	c.473G>T	p.Trp158Leu	missense_variant	5/8	ENST00000261024.7	NP_055400.1
SLC40A1	XM_047444066.1	c.353G>T	p.Trp118Leu	missense_variant	5/8		XP_047300022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC40A1	ENST00000261024.7	c.473G>T	p.Trp158Leu	missense_variant	5/8	1	NM_014585.6	ENSP00000261024	P1
SLC40A1	ENST00000427241.5	c.473G>T	p.Trp158Leu	missense_variant	7/8	5		ENSP00000390005

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:2 Other:1

Uncertain significance, no assertion criteria provided	literature only	Richard Lifton Laboratory, Yale University School of Medicine	-	- -
not provided, no classification provided	literature only	Laboratoire de Génétique Moléculaire, CHU Pontchaillou	-	- -
Uncertain significance, flagged submission	literature only	Richard Lifton Laboratory, Yale University School of Medicine	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.9	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-13	D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.048	D;.
Polyphen		0.52	P;.
Vest4		0.97
MutPred		0.91		Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);
MVP		0.90
MPC		1.6
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.96

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: rs387907375; hg19: chr2-190436482;