rs10421768

Variant names:

• chr19-35281996-A-G
• rs10421768
• ENST00000598398.5:c.-84-498A>G

Variant summary

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

The ENST00000598398.5(HAMP):​c.-84-498A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 152,150 control chromosomes in the GnomAD database, including 3,489 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.21 (3489 hom., cov: 33)
• Consequence: HAMP ENST00000598398.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.01
• Publications: 48 publications found

Genes affected

HAMP (HGNC:15598): (hepcidin antimicrobial peptide) The product encoded by this gene is involved in the maintenance of iron homeostasis, and it is necessary for the regulation of iron storage in macrophages, and for intestinal iron absorption. The preproprotein is post-translationally cleaved into mature peptides of 20, 22 and 25 amino acids, and these active peptides are rich in cysteines, which form intramolecular bonds that stabilize their beta-sheet structures. These peptides exhibit antimicrobial activity against bacteria and fungi. Mutations in this gene cause hemochromatosis type 2B, also known as juvenile hemochromatosis, a disease caused by severe iron overload that results in cardiomyopathy, cirrhosis, and endocrine failure. [provided by RefSeq, Oct 2014]

HAMP Gene-Disease associations (from GenCC):

• hemochromatosis type 2B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hemochromatosis type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000307628 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-35281996-A-G is Benign according to our data. Variant chr19-35281996-A-G is described in ClinVar as Benign. ClinVar VariationId is 1168056.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000598398.5. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAMP	ENST00000598398.5	TSL:2	c.-84-498A>G		intron	N/A	ENSP00000471894.1
	ENSG00000307628	ENST00000827558.1		n.392-1123T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31668 AN: 152032 Hom.: 3494 Cov.: 33

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.0169

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.267

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.235

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

GnomAD4 genome AF: 0.208 AC: 31669 AN: 152150 Hom.: 3489 Cov.: 33 AF XY: 0.208 AC XY: 15483 AN XY: 74372

African (AFR) AF: 0.185 AC: 7674 AN: 41474

American (AMR) AF: 0.172 AC: 2624 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 656 AN: 3472

East Asian (EAS) AF: 0.0170 AC: 88 AN: 5184

South Asian (SAS) AF: 0.218 AC: 1053 AN: 4830

European-Finnish (FIN) AF: 0.267 AC: 2826 AN: 10578

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15933 AN: 68008

Other (OTH) AF: 0.232 AC: 490 AN: 2116

Alfa AF: 0.221 Hom.: 9213

Bravo AF: 0.196

Asia WGS AF: 0.137 AC: 475 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary hemochromatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.27
DANN	Benign	0.19
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10421768; hg19: chr19-35772899;