chr1-146018957-G-A

Variant names:

• chr1-146018957-G-A
• rs10218795
• NM_213653.4:c.657+218C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_213653.4(HJV):​c.657+218C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 152,158 control chromosomes in the GnomAD database, including 2,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.15 (2981 hom., cov: 32)
• Consequence: HJV NM_213653.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.114
• Publications: 20 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, Labcorp Genetics (formerly Invitae), G2P
• hemochromatosis type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-146018957-G-A is Benign according to our data. Variant chr1-146018957-G-A is described in ClinVar as [Benign]. Clinvar id is 1182280.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HJV	NM_213653.4	c.657+218C>T		intron_variant	Intron 3 of 3	ENST00000336751.11	NP_998818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HJV	ENST00000336751.11	c.657+218C>T		intron_variant	Intron 3 of 3	2	NM_213653.4	ENSP00000337014.5

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22256 AN: 152040 Hom.: 2969 Cov.: 32

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.0652

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0408

Gnomad OTH AF: 0.125

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.147 AC: 22315 AN: 152158 Hom.: 2981 Cov.: 32 AF XY: 0.148 AC XY: 10988 AN XY: 74390

African (AFR) AF: 0.343 AC: 14238 AN: 41456

American (AMR) AF: 0.169 AC: 2581 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0418 AC: 145 AN: 3472

East Asian (EAS) AF: 0.176 AC: 909 AN: 5172

South Asian (SAS) AF: 0.129 AC: 621 AN: 4832

European-Finnish (FIN) AF: 0.0652 AC: 692 AN: 10606

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0408 AC: 2776 AN: 68018

Other (OTH) AF: 0.129 AC: 272 AN: 2112

Alfa AF: 0.0835 Hom.: 3201

Bravo AF: 0.163

Asia WGS AF: 0.208 AC: 720 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.80
DANN	Benign	0.63
PhyloP100		0.11

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

Other links and lift over

dbSNP: rs10218795; hg19: chr1-145416056;