rs104893670

Variant names:

• chr2-189565568-C-A
• rs104893670
• NM_014585.6:c.546G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-189565568-C-A
• chr2-189565568-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_014585.6(SLC40A1):​c.546G>T​(p.Gln182His) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q182E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC40A1 NM_014585.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.27
• Publications: 13 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: Pathogenic. The variant received 11 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, 5 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 chr2-189565570-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 488155.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 2-189565568-C-A is Pathogenic according to our data. Variant chr2-189565568-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 5413.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC40A1	NM_014585.6	MANE Select	c.546G>T	p.Gln182His	missense	Exon 6 of 8	NP_055400.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC40A1	ENST00000261024.7	TSL:1 MANE Select	c.546G>T	p.Gln182His	missense	Exon 6 of 8	ENSP00000261024.3
	SLC40A1	ENST00000427241.5	TSL:5	c.546G>T	p.Gln182His	missense	Exon 8 of 8	ENSP00000390005.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hemochromatosis type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		2.3
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.86
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.87		Loss of MoRF binding (P = 0.1092)
MVP		0.93
MPC		1.3
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.74
gMVP		0.92
Mutation Taster		=36/64	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104893670; hg19: chr2-190430294; COSMIC: COSV53722374;