NM_014585.6:c.744G>C

Variant names:

• chr2-189565370-C-G
• rs11568350
• NM_014585.6:c.744G>C

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.744G>C​(p.Gln248His) 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. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q248L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC40A1 NM_014585.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.232
• 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=0.15431654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC40A1	NM_014585.6	c.744G>C	p.Gln248His	missense_variant	Exon 6 of 8	ENST00000261024.7	NP_055400.1
SLC40A1	XM_047444066.1	c.624G>C	p.Gln208His	missense_variant	Exon 6 of 8		XP_047300022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC40A1	ENST00000261024.7	c.744G>C	p.Gln248His	missense_variant	Exon 6 of 8	1	NM_014585.6	ENSP00000261024.3
SLC40A1	ENST00000427241.5	c.*143G>C		downstream_gene_variant		5		ENSP00000390005.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.23
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.34
Sift	Benign	0.13	T
Sift4G	Benign	0.22	T
Polyphen		0.010	B
Vest4		0.098
MutPred		0.067		Loss of helix (P = 0.2022);
MVP		0.51
MPC		0.45
ClinPred		0.24	T
GERP RS		0.59
Varity_R		0.096
gMVP		0.63
Mutation Taster		=91/9	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

dbSNP: rs11568350; hg19: chr2-190430096;