2-189561901-G-T

Variant names:

• chr2-189561901-G-T
• NM_014585.6:c.1693C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45
• Publications: 0 publications found

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

ACMG classification

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
SLC40A1	NM_014585.6	c.1693C>A	p.Gln565Lys	missense_variant	Exon 8 of 8	ENST00000261024.7	NP_055400.1
SLC40A1	XM_047444066.1	c.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
SLC40A1	ENST00000261024.7	c.1693C>A	p.Gln565Lys	missense_variant	Exon 8 of 8	1	NM_014585.6	ENSP00000261024.3

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

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

Other links and lift over

hg19: chr2-190426627;