Genetic Variant SLC40A1:p.Asn144His (chr2-189571799-T-G) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_014585.6(SLC40A1):c.430A>C(p.Asn144His) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N144D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SLC40A1
NM_014585.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.83

Publications

31 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: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, G2P, Orphanet, Ambry Genetics

SLC40A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a helix (size 29) in uniprot entity S40A1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chr2-189571799-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 801843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

PP5

Variant 2-189571799-T-G is Pathogenic according to our data. Variant chr2-189571799-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 5410.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC40A1	NM_014585.6	MANE Select	c.430A>C	p.Asn144His	missense	Exon 5 of 8	NP_055400.1	Q9NP59

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC40A1	ENST00000261024.7	TSL:1 MANE Select	c.430A>C	p.Asn144His	missense	Exon 5 of 8	ENSP00000261024.3	Q9NP59
SLC40A1	ENST00000852923.1		c.430A>C	p.Asn144His	missense	Exon 7 of 10	ENSP00000522982.1
SLC40A1	ENST00000852924.1		c.430A>C	p.Asn144His	missense	Exon 6 of 9	ENSP00000522983.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hemochromatosis type 4 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.055

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.66

MutationAssessor

Uncertain

2.4

PhyloP100

7.8

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.65

Sift

Benign

0.11

Sift4G

Benign

0.097

Polyphen

0.93

Vest4

0.92

MutPred

0.96

Gain of relative solvent accessibility (P = 0.1259)

MVP

0.76

MPC

0.62

ClinPred

0.95

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.59

gMVP

0.93

Mutation Taster

=16/84

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over