rs104893662

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate

The NM_014585.6(SLC40A1):​c.430A>T​(p.Asn144Tyr) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N144T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SLC40A1
NM_014585.6 missense

Scores

9
9
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.83
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 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.971
PP5
Variant 2-189571799-T-A is Pathogenic according to our data. Variant chr2-189571799-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 240918.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC40A1NM_014585.6 linkuse as main transcriptc.430A>T p.Asn144Tyr missense_variant 5/8 ENST00000261024.7 NP_055400.1 Q9NP59
SLC40A1XM_047444066.1 linkuse as main transcriptc.310A>T p.Asn104Tyr missense_variant 5/8 XP_047300022.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC40A1ENST00000261024.7 linkuse as main transcriptc.430A>T p.Asn144Tyr missense_variant 5/81 NM_014585.6 ENSP00000261024.3 Q9NP59
SLC40A1ENST00000427241.5 linkuse as main transcriptc.430A>T p.Asn144Tyr missense_variant 7/85 ENSP00000390005.1 E7ES28

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hemochromatosis type 4 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 11, 2023This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 144 of the SLC40A1 protein (p.Asn144Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary hemochromatosis (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 240918). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC40A1 protein function with a positive predictive value of 80%. This variant disrupts the p.Asn144 amino acid residue in SLC40A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11431687, 12865285, 15030991, 15831700, 16440176, 19383972). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.40
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.75
D;.
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Pathogenic
3.1
M;.
PrimateAI
Uncertain
0.74
T
PROVEAN
Uncertain
-4.2
D;D
REVEL
Pathogenic
0.84
Sift
Uncertain
0.0090
D;D
Sift4G
Uncertain
0.055
T;.
Polyphen
1.0
D;.
Vest4
0.86
MutPred
0.91
Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);
MVP
0.93
MPC
1.4
ClinPred
0.99
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.67
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

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

Other links and lift over

dbSNP: rs104893662; hg19: chr2-190436525; API