chr19-35282506-C-T

Variant names:

• chr19-35282506-C-T
• rs367646034
• ENST00000598398:c.-72C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The ENST00000598398(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_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: -0.475

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

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000919 (140/152350) while in subpopulation SAS AF = 0.00332 (16/4824). AF 95% confidence interval is 0.00208. There are 2 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAMP	NM_021175.4	c.-72C>T		upstream_gene_variant		ENST00000222304.5	NP_066998.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAMP	ENST00000598398	c.-72C>T		5_prime_UTR_variant	Exon 2 of 4	2		ENSP00000471894.1
HAMP	ENST00000222304.5	c.-72C>T		upstream_gene_variant		1	NM_021175.4	ENSP00000222304.2
HAMP	ENST00000593580.1	n.-11C>T		upstream_gene_variant		6

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152232 Hom.: 2 Cov.: 32

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.: 2 Cov.: 16 AF XY: 0.00124 AC XY: 677 AN XY: 548152

Gnomad4 AFR exome AF: 0.000193 AC: 5 AN: 25850

Gnomad4 AMR exome AF: 0.00117 AC: 52 AN: 44280

Gnomad4 ASJ exome AF: 0.00111 AC: 26 AN: 23514

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 37848

Gnomad4 SAS exome AF: 0.00237 AC: 186 AN: 78482

Gnomad4 FIN exome AF: 0.000113 AC: 6 AN: 52934

Gnomad4 NFE exome AF: 0.00110 AC: 830 AN: 752150

Gnomad4 Remaining exome AF: 0.00145 AC: 69 AN: 47450

GnomAD4 genome AF: 0.000919 AC: 140 AN: 152350 Hom.: 2 Cov.: 32 AF XY: 0.000966 AC XY: 72 AN XY: 74502

Gnomad4 AFR AF: 0.000240 AC: 0.000240489 AN: 0.000240489

Gnomad4 AMR AF: 0.000588 AC: 0.000588005 AN: 0.000588005

Gnomad4 ASJ AF: 0.000865 AC: 0.000864553 AN: 0.000864553

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00332 AC: 0.00331675 AN: 0.00331675

Gnomad4 FIN AF: 0.0000941 AC: 0.0000941088 AN: 0.0000941088

Gnomad4 NFE AF: 0.00144 AC: 0.00144041 AN: 0.00144041

Gnomad4 OTH AF: 0.000948 AC: 0.000947867 AN: 0.000947867

Alfa AF: 0.00122 Hom.: 1

Bravo AF: 0.000899

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hemochromatosis type 2B Uncertain:1

Mar 02, 2023

Clinical Genetics, Synlab MVZ Humangenetik Freiburg

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Aug 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.82
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs367646034; hg19: chr19-35773409;