1-146018566-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_213653.4(HJV):c.792G>C(p.Ser264=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00089 in 1,614,146 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S264S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0048 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (4 hom.)
• Consequence: HJV NM_213653.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.302

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 1-146018566-C-G is Benign according to our data. Variant chr1-146018566-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 536407.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BP7: Synonymous conserved (PhyloP=-0.302 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00482 (734/152256) while in subpopulation AFR AF= 0.0168 (698/41538). AF 95% confidence interval is 0.0158. There are 5 homozygotes in gnomad4. There are 335 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HJV	NM_213653.4	c.792G>C	p.Ser264=	synonymous_variant	4/4	ENST00000336751.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HJV	ENST00000336751.11	c.792G>C	p.Ser264=	synonymous_variant	4/4	2	NM_213653.4	P1

Frequencies

GnomAD3 genomes AF: 0.00484 AC: 737 AN: 152138 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00120 AC: 303 AN: 251494 Hom.: 2 AF XY: 0.000853 AC XY: 116 AN XY: 135922

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000480 AC: 702 AN: 1461890 Hom.: 4 Cov.: 32 AF XY: 0.000436 AC XY: 317 AN XY: 727244

Gnomad4 AFR exome AF: 0.0171

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00482 AC: 734 AN: 152256 Hom.: 5 Cov.: 32 AF XY: 0.00450 AC XY: 335 AN XY: 74448

Gnomad4 AFR AF: 0.0168

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000246 Hom.: 0

Bravo AF: 0.00556

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hemochromatosis type 2A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	4.5
Dann	Benign	0.64

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

LitVar

Other links and lift over

dbSNP: rs35710964; hg19: chr1-145416447;