1-146019625-GCCTCCTCCT-GCCTCCTCCTCCT

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

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

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.144

Publications

2 publications found

Variant links:

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, Labcorp Genetics (formerly Invitae), G2P
hemochromatosis type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HJV links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HJV	NM_213653.4 link	c.204_206dupAGG	p.Gly69dup	disruptive_inframe_insertion	Exon 3 of 4	ENST00000336751.11	NP_998818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HJV	ENST00000336751.11 link	c.204_206dupAGG	p.Gly69dup	disruptive_inframe_insertion	Exon 3 of 4	2	NM_213653.4	ENSP00000337014.5

Frequencies

GnomAD3 genomes

AF:

0.00357

AC:

543

AN:

151918

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.000806

AC XY:

584

AN XY:

724928

show subpopulations

African (AFR)

AF:

0.0116

AC:

388

AN:

33404

American (AMR)

AF:

0.00134

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.000126

AC:

AN:

39668

South Asian (SAS)

AF:

0.000650

AC:

AN:

86142

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

53094

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.000464

AC:

514

AN:

1107860

Other (OTH)

AF:

0.00131

AC:

AN:

60216

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

140

209

279

349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00357

AC:

543

AN:

152034

Hom.:

Cov.:

AF XY:

0.00354

AC XY:

263

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0107

AC:

442

AN:

41478

American (AMR)

AF:

0.00354

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.000416

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.000755

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000427

AC:

AN:

67938

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000254

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HJV: PM4:Supporting, BS1 -

Hemochromatosis type 2A

Benign:1

Sep 26, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

HJV-related disorder

Benign:1

Oct 10, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.14

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over