rs8101606

Positions:

• chr19-35283653-A-C
• chr19-35283653-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021175.4(HAMP):​c.90+986A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 152,320 control chromosomes in the GnomAD database, including 3,350 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3347 hom., cov: 32)
  • Exomes 𝑓: 0.18 (3 hom.)
• Consequence: HAMP NM_021175.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0730

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAMP	NM_021175.4	c.90+986A>C		intron_variant		ENST00000222304.5	NP_066998.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAMP	ENST00000222304.5	c.90+986A>C		intron_variant		1	NM_021175.4	ENSP00000222304	P1
HAMP	ENST00000598398.5	c.90+986A>C		intron_variant		2		ENSP00000471894	P1
HAMP	ENST00000593580.1	n.1137A>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30805 AN: 152014 Hom.: 3352 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.0168

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.267

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.230

GnomAD4 exome AF: 0.181 AC: 34 AN: 188 Hom.: 3 Cov.: 0 AF XY: 0.158 AC XY: 18 AN XY: 114

Gnomad4 EAS exome AF: 0.125

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.180

Gnomad4 NFE exome AF: 0.170

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.203 AC: 30808 AN: 152132 Hom.: 3347 Cov.: 32 AF XY: 0.203 AC XY: 15065 AN XY: 74366

Gnomad4 AFR AF: 0.165

Gnomad4 AMR AF: 0.169

Gnomad4 ASJ AF: 0.190

Gnomad4 EAS AF: 0.0168

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.267

Gnomad4 NFE AF: 0.235

Gnomad4 OTH AF: 0.227

Alfa AF: 0.186 Hom.: 1167

Bravo AF: 0.190

Asia WGS AF: 0.135 AC: 468 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs8101606; hg19: chr19-35774556;