Genetic Variant NM_014585.6:c.430A>G (chr2-189571799-T-C) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_014585.6(SLC40A1):c.430A>G(p.Asn144Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,588 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N144Y) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC40A1
NM_014585.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts 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 18 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-A is described in ClinVar as Pathogenic. ClinVar VariationId is 240918.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

PP5

Variant 2-189571799-T-C is Pathogenic according to our data. 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.

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>G	p.Asn144Asp	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>G	p.Asn144Asp	missense	Exon 5 of 8	ENSP00000261024.3	Q9NP59
SLC40A1	ENST00000852923.1		c.430A>G	p.Asn144Asp	missense	Exon 7 of 10	ENSP00000522982.1
SLC40A1	ENST00000852924.1		c.430A>G	p.Asn144Asp	missense	Exon 6 of 9	ENSP00000522983.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460588

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726688

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33442

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39610

South Asian (SAS)

AF:

0.00

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110952

Other (OTH)

AF:

0.00

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hemochromatosis type 4 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.085

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.63

MutationAssessor

Pathogenic

3.1

PhyloP100

7.8

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.69

Sift

Benign

0.067

Sift4G

Benign

0.072

Polyphen

1.0

Vest4

0.92

MutPred

0.94

Gain of relative solvent accessibility (P = 0.09)

MVP

0.90

MPC

0.78

ClinPred

0.97

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.97

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.23

Position offset: -1

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