1-146019625-GCCTCCTCCT-GCCTCCTCCTCCT

Variant names:

• chr1-146019625-G-GCCT
• rs587644102
• NM_213653.4:c.204_206dupAGG

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_213653.4(HJV):​c.204_206dupAGG​(p.Gly69dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,608,982 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G69G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (3 hom.)
• Consequence: HJV NM_213653.4 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.144
• Publications: 2 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: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hemochromatosis type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_213653.4
• BP6: Variant 1-146019625-G-GCCT is Benign according to our data. Variant chr1-146019625-G-GCCT is described in ClinVar as Likely_benign. ClinVar VariationId is 219585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00357 (543/152034) while in subpopulation AFR AF = 0.0107 (442/41478). AF 95% confidence interval is 0.00984. There are 2 homozygotes in GnomAd4. There are 263 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.204_206dupAGG	p.Gly69dup	disruptive_inframe_insertion	Exon 3 of 4	NP_998818.1	Q6ZVN8-1
	HJV	NM_001379352.1		c.204_206dupAGG	p.Gly69dup	disruptive_inframe_insertion	Exon 3 of 4	NP_001366281.1	Q6ZVN8-1
	HJV	NM_145277.5		c.-136_-134dupAGG		5_prime_UTR	Exon 2 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.204_206dupAGG	p.Gly69dup	disruptive_inframe_insertion	Exon 3 of 4	ENSP00000337014.5	Q6ZVN8-1
	HJV	ENST00000357836.5	TSL:1	c.-136_-134dupAGG		5_prime_UTR	Exon 2 of 3	ENSP00000350495.5	Q6ZVN8-2
	HJV	ENST00000497365.5	TSL:1	c.-22+70_-22+72dupAGG		intron	N/A	ENSP00000421820.1	Q6ZVN8-3

Frequencies

GnomAD3 genomes AF: 0.00357 AC: 543 AN: 151918 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000427

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00137 AC: 338 AN: 246272 AF XY: 0.00123

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000219

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.000590

Gnomad OTH exome AF: 0.000334

GnomAD4 exome AF: 0.000805 AC: 1173 AN: 1456948 Hom.: 3 Cov.: 47 AF XY: 0.000806 AC XY: 584 AN XY: 724928

African (AFR) AF: 0.0116 AC: 388 AN: 33404

American (AMR) AF: 0.00134 AC: 60 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39668

South Asian (SAS) AF: 0.000650 AC: 56 AN: 86142

European-Finnish (FIN) AF: 0.00122 AC: 65 AN: 53094

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5748

European-Non Finnish (NFE) AF: 0.000464 AC: 514 AN: 1107860

Other (OTH) AF: 0.00131 AC: 79 AN: 60216

GnomAD4 genome AF: 0.00357 AC: 543 AN: 152034 Hom.: 2 Cov.: 32 AF XY: 0.00354 AC XY: 263 AN XY: 74334

African (AFR) AF: 0.0107 AC: 442 AN: 41478

American (AMR) AF: 0.00354 AC: 54 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4808

European-Finnish (FIN) AF: 0.000755 AC: 8 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000427 AC: 29 AN: 67938

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.000254 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hemochromatosis type 2A (1)
-	-	1	HJV-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.14

Splicing

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

Other links and lift over

dbSNP: rs587644102; hg19: chr1-145415388;