rs28940586

Positions:

• chr1-146019594-A-C
• chr1-146019594-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_213653.4(HJV):​c.238T>G​(p.Cys80Gly) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C80R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HJV NM_213653.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.21

Genes affected

HJV (HGNC:4887): (hemojuvelin BMP co-receptor) The product of this gene is involved in iron metabolism. It may be a component of the signaling pathway which activates hepcidin or it may act as a modulator of hepcidin expression. It could also represent the cellular receptor for hepcidin. Two uORFs in the 5' UTR negatively regulate the expression and activity of the encoded protein. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. Defects in this gene are the cause of hemochromatosis type 2A, also called juvenile hemochromatosis (JH). JH is an early-onset autosomal recessive disorder due to severe iron overload resulting in hypogonadotrophic hypogonadism, hepatic fibrosis or cirrhosis and cardiomyopathy, occurring typically before age of 30. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a helix (size 15) in uniprot entity RGMC_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_213653.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-146019594-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2369.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 1-146019594-A-C is Pathogenic according to our data. Variant chr1-146019594-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216012.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HJV	NM_213653.4	c.238T>G	p.Cys80Gly	missense_variant	3/4	ENST00000336751.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HJV	ENST00000336751.11	c.238T>G	p.Cys80Gly	missense_variant	3/4	2	NM_213653.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2015

In summary, this is a novel missense change observed in a homozygous state in a classically affected individual. The effect of this variant on protein function is uncertain, but other amino acid substitutions affecting this residue have been reported to be pathogenic. For these reasons, this variant has been classified as Likely Pathogenic. While this Cys80Gly variant has not been reported in the literature, other missense changes at this codon (Cys80Arg, Cys80Tyr) have been reported in patients affected with hemochromatosis (PMID: 14982867, 19342478). The Cys80Arg change has also been shown to disrupt HFE2 function in vitro (PMID: 18827264). This indicates that the Cys80 amino acid residue may be critical for proper protein function. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been published in the literature and is not present in population databases. This sequence change replaces cysteine with glycine at codon 80 of the HFE2 protein (p.Cys80Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.99	D;.
LIST_S2	Benign	0.63	T;T
MetaRNN	Pathogenic	0.98	D;D
PROVEAN	Pathogenic	-11	D;D
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;.
Vest4		0.94
gMVP		1.0

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: rs28940586; hg19: chr1-145415419;