2-189561901-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014585.6(SLC40A1):​c.1693C>A​(p.Gln565Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

SLC40A1
NM_014585.6 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.45

Publications

0 publications found
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]
SLC40A1 Gene-Disease associations (from GenCC):
  • hemochromatosis type 4
    Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.105605304).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC40A1NM_014585.6 linkc.1693C>A p.Gln565Lys missense_variant Exon 8 of 8 ENST00000261024.7 NP_055400.1 Q9NP59
SLC40A1XM_047444066.1 linkc.1573C>A p.Gln525Lys missense_variant Exon 8 of 8 XP_047300022.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC40A1ENST00000261024.7 linkc.1693C>A p.Gln565Lys missense_variant Exon 8 of 8 1 NM_014585.6 ENSP00000261024.3 Q9NP59

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Apr 28, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1693C>A (p.Q565K) alteration is located in exon 8 (coding exon 8) of the SLC40A1 gene. This alteration results from a C to A substitution at nucleotide position 1693, causing the glutamine (Q) at amino acid position 565 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
0.0090
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
2.6
DANN
Benign
0.59
DEOGEN2
Benign
0.15
T
Eigen
Benign
-0.97
Eigen_PC
Benign
-0.94
FATHMM_MKL
Benign
0.69
D
LIST_S2
Benign
0.67
T
M_CAP
Benign
0.031
D
MetaRNN
Benign
0.11
T
MetaSVM
Benign
-0.53
T
MutationAssessor
Benign
1.9
L
PhyloP100
1.4
PrimateAI
Benign
0.35
T
PROVEAN
Benign
0.11
N
REVEL
Benign
0.18
Sift
Benign
0.26
T
Sift4G
Benign
0.32
T
Polyphen
0.020
B
Vest4
0.20
MutPred
0.18
Gain of ubiquitination at Q565 (P = 0.0048);
MVP
0.57
MPC
0.62
ClinPred
0.062
T
GERP RS
-0.31
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.038
gMVP
0.54
Mutation Taster
=98/2
polymorphism

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

Other links and lift over

hg19: chr2-190426627; API