19-35282425-C-T

Position:

• chr19-35282425-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000598398.5(HAMP):​c.-84-69C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 762,254 control chromosomes in the GnomAD database, including 8 homozygotes. 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 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (7 hom.)
• Consequence: HAMP ENST00000598398.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 2.02

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAMP	ENST00000598398.5	c.-84-69C>T		intron_variant		2		ENSP00000471894	P1

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 426 AN: 152146 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00629

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00381

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.00269 AC: 1641 AN: 609990 Hom.: 7 Cov.: 6 AF XY: 0.00277 AC XY: 919 AN XY: 331630

Gnomad4 AFR exome AF: 0.000641

Gnomad4 AMR exome AF: 0.00330

Gnomad4 ASJ exome AF: 0.00133

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000571

Gnomad4 FIN exome AF: 0.00119

Gnomad4 NFE exome AF: 0.00373

Gnomad4 OTH exome AF: 0.00211

GnomAD4 genome AF: 0.00280 AC: 426 AN: 152264 Hom.: 1 Cov.: 32 AF XY: 0.00269 AC XY: 200 AN XY: 74444

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00628

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00381

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.00269

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2021

- -

Hemochromatosis type 2B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 10, 2021

- -

Hereditary hemochromatosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs142126068; hg19: chr19-35773328;