1-146019740-G-C

Variant names:

• chr1-146019740-G-C
• rs56025621
• NM_213653.4:c.98-6C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_213653.4(HJV):​c.98-6C>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0246 in 1,613,914 control chromosomes in the GnomAD database, including 621 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (45 hom., cov: 32)
  • Exomes 𝑓: 0.025 (576 hom.)
• Consequence: HJV NM_213653.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.51
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 1-146019740-G-C is Benign according to our data. Variant chr1-146019740-G-C is described in ClinVar as Benign. ClinVar VariationId is 220423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0177 (2692/152202) while in subpopulation NFE AF = 0.0312 (2119/68014). AF 95% confidence interval is 0.03. There are 45 homozygotes in GnomAd4. There are 1208 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 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.98-6C>G		splice_region intron	N/A	NP_998818.1	Q6ZVN8-1
	HJV	NM_001379352.1		c.98-6C>G		splice_region intron	N/A	NP_001366281.1	Q6ZVN8-1
	HJV	NM_145277.5		c.-242-6C>G		splice_region intron	N/A	NP_660320.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HJV	ENST00000336751.11	TSL:2 MANE Select	c.98-6C>G		splice_region intron	N/A	ENSP00000337014.5	Q6ZVN8-1
	HJV	ENST00000357836.5	TSL:1	c.-242-6C>G		splice_region intron	N/A	ENSP00000350495.5	Q6ZVN8-2
	HJV	ENST00000497365.5	TSL:1	c.-58-6C>G		splice_region intron	N/A	ENSP00000421820.1	Q6ZVN8-3

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2694 AN: 152084 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.00495

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00885

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0312

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0177 AC: 4419 AN: 250350 AF XY: 0.0179

Gnomad AFR exome AF: 0.00414

Gnomad AMR exome AF: 0.00732

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0163

Gnomad NFE exome AF: 0.0294

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0253 AC: 37034 AN: 1461712 Hom.: 576 Cov.: 37 AF XY: 0.0251 AC XY: 18250 AN XY: 727164

African (AFR) AF: 0.00412 AC: 138 AN: 33474

American (AMR) AF: 0.00789 AC: 353 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00187 AC: 49 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0108 AC: 928 AN: 86252

European-Finnish (FIN) AF: 0.0169 AC: 902 AN: 53378

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5764

European-Non Finnish (NFE) AF: 0.0301 AC: 33413 AN: 1111906

Other (OTH) AF: 0.0203 AC: 1228 AN: 60384

GnomAD4 genome AF: 0.0177 AC: 2692 AN: 152202 Hom.: 45 Cov.: 32 AF XY: 0.0162 AC XY: 1208 AN XY: 74406

African (AFR) AF: 0.00494 AC: 205 AN: 41522

American (AMR) AF: 0.00883 AC: 135 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00932 AC: 45 AN: 4830

European-Finnish (FIN) AF: 0.0150 AC: 159 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0312 AC: 2119 AN: 68014

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.0251 Hom.: 22

Bravo AF: 0.0156

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hemochromatosis type 2A (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.82
PhyloP100		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs56025621; hg19: chr1-145415273;