2-189571799-T-C

Position:

• chr2-189571799-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N144T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC40A1 NM_014585.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.83

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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 [Likely_pathogenic]. Clinvar id is 801843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC40A1	NM_014585.6	c.430A>G	p.Asn144Asp	missense_variant	5/8	ENST00000261024.7	NP_055400.1
SLC40A1	XM_047444066.1	c.310A>G	p.Asn104Asp	missense_variant	5/8		XP_047300022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC40A1	ENST00000261024.7	c.430A>G	p.Asn144Asp	missense_variant	5/8	1	NM_014585.6	ENSP00000261024.3
SLC40A1	ENST00000427241.5	c.430A>G	p.Asn144Asp	missense_variant	7/8	5		ENSP00000390005.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460588 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726688

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hemochromatosis type 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Mar 14, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 25, 2021	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asn144 amino acid residue in SLC40A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11431687, 15030991, 12865285, 16440176, 15831700). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this variant affects SLC40A1 protein function (PMID: 15831700, 19383972). This variant has been observed in individual(s) with hereditary hemochromatosis (PMID: 15030991, Invitae). ClinVar contains an entry for this variant (Variation ID: 801843). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with aspartic acid at codon 144 of the SLC40A1 protein (p.Asn144Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.085	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.067	T;D
Sift4G	Benign	0.072	T;.
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.94		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP		0.90
MPC		0.78
ClinPred		0.97	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.97

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

LitVar

Other links and lift over

dbSNP: rs104893662; hg19: chr2-190436525;