1-146018094-A-T

Variant names:

• chr1-146018094-A-T
• NM_213653.4:c.1264T>A
• HJV p.Trp422Arg

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_213653.4(HJV):​c.1264T>A​(p.Trp422Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HJV NM_213653.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.89
• Publications: 0 publications found

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]

HJV Gene-Disease associations (from GenCC):

• hemochromatosis type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hemochromatosis type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213653.4. 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
	HJV	NM_213653.4	MANE Select	c.1264T>A	p.Trp422Arg	missense	Exon 4 of 4	NP_998818.1	Q6ZVN8-1
	HJV	NM_001379352.1		c.1264T>A	p.Trp422Arg	missense	Exon 4 of 4	NP_001366281.1	Q6ZVN8-1
	HJV	NM_145277.5		c.925T>A	p.Trp309Arg	missense	Exon 3 of 3	NP_660320.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HJV	ENST00000336751.11	TSL:2 MANE Select	c.1264T>A	p.Trp422Arg	missense	Exon 4 of 4	ENSP00000337014.5	Q6ZVN8-1
	HJV	ENST00000357836.5	TSL:1	c.925T>A	p.Trp309Arg	missense	Exon 3 of 3	ENSP00000350495.5	Q6ZVN8-2
	HJV	ENST00000497365.5	TSL:1	c.586T>A	p.Trp196Arg	missense	Exon 3 of 3	ENSP00000421820.1	Q6ZVN8-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
LIST_S2	Benign	0.60	T
MetaRNN	Uncertain	0.52	D
PhyloP100		1.9
PROVEAN	Uncertain	-2.6	D
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.058	T
gMVP		0.95

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-145416919;