rs786205063

Variant names:

• chr1-146018372-CGAGA-C
• rs786205063
• NM_213653.4:c.982_985delTCTC

Your query was ambiguous. Multiple possible variants found:

• chr1-146018372-CGAGA-C
• chr1-146018372-CGAGA-CGA

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_213653.4(HJV):​c.982_985delTCTC​(p.Ser328AspfsTer10) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HJV NM_213653.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.83
• Publications: 9 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hemochromatosis type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-146018372-CGAGA-C is Pathogenic according to our data. Variant chr1-146018372-CGAGA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2372.Status of the report is no_assertion_criteria_provided, 0 stars.

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.982_985delTCTC	p.Ser328AspfsTer10	frameshift	Exon 4 of 4	NP_998818.1	Q6ZVN8-1
	HJV	NM_001379352.1		c.982_985delTCTC	p.Ser328AspfsTer10	frameshift	Exon 4 of 4	NP_001366281.1	Q6ZVN8-1
	HJV	NM_145277.5		c.643_646delTCTC	p.Ser215AspfsTer10	frameshift	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.982_985delTCTC	p.Ser328AspfsTer10	frameshift	Exon 4 of 4	ENSP00000337014.5	Q6ZVN8-1
	HJV	ENST00000357836.5	TSL:1	c.643_646delTCTC	p.Ser215AspfsTer10	frameshift	Exon 3 of 3	ENSP00000350495.5	Q6ZVN8-2
	HJV	ENST00000497365.5	TSL:1	c.304_307delTCTC	p.Ser102AspfsTer10	frameshift	Exon 3 of 3	ENSP00000421820.1	Q6ZVN8-3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hemochromatosis type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8

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

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

Other links and lift over

dbSNP: rs786205063;

hg19: chr1-145416641;