Genetic Variant HJV:p.Ala144Ala (chr1-146019400-G-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_213653.4(HJV):c.432C>G(p.Ala144Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,613,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 0 hom. )

Consequence

HJV
NM_213653.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.188

Publications

0 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, ClinGen, 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 1-146019400-G-C is Benign according to our data. Variant chr1-146019400-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 536406.

BP7

Synonymous conserved (PhyloP=0.188 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00063 (96/152374) while in subpopulation NFE AF = 0.00103 (70/68024). AF 95% confidence interval is 0.000835. There are 0 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HJV	NM_213653.4	MANE Select	c.432C>G	p.Ala144Ala	synonymous	Exon 3 of 4	NP_998818.1	Q6ZVN8-1
HJV	NM_001379352.1		c.432C>G	p.Ala144Ala	synonymous	Exon 3 of 4	NP_001366281.1	Q6ZVN8-1
HJV	NM_145277.5		c.93C>G	p.Ala31Ala	synonymous	Exon 2 of 3	NP_660320.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HJV	ENST00000336751.11	TSL:2 MANE Select	c.432C>G	p.Ala144Ala	synonymous	Exon 3 of 4	ENSP00000337014.5	Q6ZVN8-1
HJV	ENST00000357836.5	TSL:1	c.93C>G	p.Ala31Ala	synonymous	Exon 2 of 3	ENSP00000350495.5	Q6ZVN8-2
HJV	ENST00000497365.5	TSL:1	c.-22+298C>G		intron	N/A	ENSP00000421820.1	Q6ZVN8-3

Frequencies

GnomAD3 genomes

AF:

0.000631

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000470

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000575

AC:

139

AN:

241672

AF XY:

0.000537

show subpopulations

Gnomad AFR exome

AF:

0.000198

Gnomad AMR exome

AF:

0.00143

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000772

Gnomad OTH exome

AF:

0.000337

GnomAD4 exome

AF:

0.00112

AC:

1638

AN:

1460988

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

781

AN XY:

726746

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33474

American (AMR)

AF:

0.00116

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26122

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.000132

AC:

AN:

52852

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00135

AC:

1504

AN:

1111820

Other (OTH)

AF:

0.00104

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

100

200

301

401

501

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

116

174

232

290

<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:

0.000630

AC:

AN:

152374

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.000288

AC:

AN:

41600

American (AMR)

AF:

0.000522

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000470

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00103

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

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:

0.000581

Hom.:

Bravo

AF:

0.000604

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hemochromatosis type 2A (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

9.0

(source)

DANN

Benign

0.77

PhyloP100

0.19

Mutation Taster

=91/9

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over