19-35284538-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_021175.4(HAMP):c.91-251A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.485 in 581,420 control chromosomes in the GnomAD database, including 71,257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.44 (15775 hom., cov: 31)
  • Exomes 𝑓: 0.50 (55482 hom.)
• Consequence: HAMP NM_021175.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0800

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-35284538-A-G is Benign according to our data. Variant chr19-35284538-A-G is described in ClinVar as [Benign]. Clinvar id is 1286974.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAMP	NM_021175.4	c.91-251A>G		intron_variant		ENST00000222304.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAMP	ENST00000222304.5	c.91-251A>G		intron_variant		1	NM_021175.4	P1
HAMP	ENST00000598398.5	c.91-251A>G		intron_variant		2		P1
HAMP	ENST00000593580.1	n.2022A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66196 AN: 151728 Hom.: 15765 Cov.: 31

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.521

Gnomad ASJ AF: 0.546

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.564

Gnomad NFE AF: 0.526

Gnomad OTH AF: 0.460

GnomAD4 exome AF: 0.502 AC: 215577 AN: 429580 Hom.: 55482 Cov.: 0 AF XY: 0.504 AC XY: 113759 AN XY: 225808

Gnomad4 AFR exome AF: 0.231

Gnomad4 AMR exome AF: 0.525

Gnomad4 ASJ exome AF: 0.549

Gnomad4 EAS exome AF: 0.346

Gnomad4 SAS exome AF: 0.514

Gnomad4 FIN exome AF: 0.487

Gnomad4 NFE exome AF: 0.528

Gnomad4 OTH exome AF: 0.498

GnomAD4 genome AF: 0.436 AC: 66237 AN: 151840 Hom.: 15775 Cov.: 31 AF XY: 0.437 AC XY: 32445 AN XY: 74172

Gnomad4 AFR AF: 0.228

Gnomad4 AMR AF: 0.521

Gnomad4 ASJ AF: 0.546

Gnomad4 EAS AF: 0.401

Gnomad4 SAS AF: 0.505

Gnomad4 FIN AF: 0.485

Gnomad4 NFE AF: 0.526

Gnomad4 OTH AF: 0.466

Alfa AF: 0.514 Hom.: 41038

Bravo AF: 0.428

Asia WGS AF: 0.478 AC: 1661 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	5.2
Dann	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs7251432; hg19: chr19-35775441;