Variant 19-35282506-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000598398.5(HAMP):c.-72C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,219,920 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00092 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

HAMP
ENST00000598398.5 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:2

Conservation

PhyloP100: -0.475

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAMP	NM_021175.4 linkuse as main transcript			upstream_gene_variant		ENST00000222304.5

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris
HAMP	ENST00000598398.5 linkuse as main transcript	c.-72C>T	5_prime_UTR_variant	2/4	2		P1
HAMP	ENST00000222304.5 linkuse as main transcript		upstream_gene_variant		1	NM_021175.4	P1
HAMP	ENST00000593580.1 linkuse as main transcript		upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.000933

AC:

142

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00145

Gnomad OTH

AF:

0.000958

GnomAD4 exome

AF:

0.00112

AC:

1200

AN:

1067570

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

677

AN XY:

548152

show subpopulations

Gnomad4 AFR exome

AF:

0.000193

Gnomad4 AMR exome

AF:

0.00117

Gnomad4 ASJ exome

AF:

0.00111

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00237

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.00110

Gnomad4 OTH exome

AF:

0.00145

GnomAD4 genome

AF:

0.000919

AC:

140

AN:

152350

Hom.:

Cov.:

AF XY:

0.000966

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000240

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00144

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.00122

Hom.:

Bravo

AF:

0.000899

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hemochromatosis type 2B

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Genetics, Synlab MVZ Humangenetik Freiburg

Mar 02, 2023

The variant was detected heterozygously in a young patient with pronounced HFE hemochromatosis, who is also homozygous for the HFE variant c.845G>A, p.(Cys282Tyr). The HAMP variant c.-72C>T, p.?, has already been described as possibly pathogenic (Biasiotto et al. 2004, HGMD Professional 2022.4). Furthermore, other regulatory mutations have already been described as causative for juvenile hemochromatosis (including Island et al. 2009). It is listed with an allele frequency of 0.11% (35x heterozygous, 1x homozygous) in control databases (dbSNP rs367646034, gnomAD v2.1.1). Heterozygous pathogenic variants in the HAMP gene have been shown to increase the risk of iron overload in HFE c.845G>A heterozygotes and increase iron load in HFE c.845G>A homozygotes (Merryweather-Clarke et al 2003, Jacolot et al 2004; Piperno et al, geneReviews 2020). We evaluate the HAMP variant c.-72C>T, p.?, as a variant of unclear significance (VUS). -

Hereditary hemochromatosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: 20

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over