rs28939076

Positions:

• chr2-189575202-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The ENST00000261024.7(SLC40A1):​c.230C>A​(p.Ala77Asp) 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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC40A1 ENST00000261024.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.07

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000261024.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 2-189575202-G-T is Pathogenic according to our data. Variant chr2-189575202-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 5411.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC40A1	NM_014585.6	c.230C>A	p.Ala77Asp	missense_variant	3/8	ENST00000261024.7	NP_055400.1
SLC40A1	XM_047444066.1	c.110C>A	p.Ala37Asp	missense_variant	3/8		XP_047300022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC40A1	ENST00000261024.7	c.230C>A	p.Ala77Asp	missense_variant	3/8	1	NM_014585.6	ENSP00000261024	P1
SLC40A1	ENST00000479598.5	n.511C>A		non_coding_transcript_exon_variant	3/4	1
SLC40A1	ENST00000427241.5	c.230C>A	p.Ala77Asp	missense_variant	5/8	5		ENSP00000390005
SLC40A1	ENST00000418714.1	n.671C>A		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hemochromatosis type 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.026	D;.
Polyphen		1.0	D;.
Vest4		1.0
MutPred		0.85		Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);
MVP		0.73
MPC		1.7
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs28939076; hg19: chr2-190439928;