rs387907376

Variant names:

• chr2-189565561-T-C
• rs387907376
• NM_014585.6:c.553A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_014585.6(SLC40A1):​c.553A>G​(p.Asn185Asp) 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 not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N185T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC40A1 NM_014585.6 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 8.02
• Publications: 4 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: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, G2P, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_014585.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-189565560-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 986327.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014585.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC40A1	NM_014585.6	MANE Select	c.553A>G	p.Asn185Asp	missense	Exon 6 of 8	NP_055400.1	Q9NP59

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC40A1	ENST00000261024.7	TSL:1 MANE Select	c.553A>G	p.Asn185Asp	missense	Exon 6 of 8	ENSP00000261024.3	Q9NP59
	SLC40A1	ENST00000852923.1		c.553A>G	p.Asn185Asp	missense	Exon 8 of 10	ENSP00000522982.1
	SLC40A1	ENST00000852924.1		c.553A>G	p.Asn185Asp	missense	Exon 7 of 9	ENSP00000522983.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.014	D
Sift4G	Benign	0.20	T
Polyphen		0.99	D
Vest4		0.94
MutPred		0.92		Loss of MoRF binding (P = 0.0771)
MVP		0.86
MPC		1.2
ClinPred		0.94	D
GERP RS		5.9
Varity_R		0.74
gMVP		0.95
Mutation Taster		=11/89	disease causing

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: rs387907376; hg19: chr2-190430287;