NM_021175.4:c.91-251A>G

Variant names:

• chr19-35284538-A-G
• rs7251432
• NM_021175.4:c.91-251A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0800
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• hemochromatosis type 2B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hemochromatosis type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000307628 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1286974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021175.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAMP	NM_021175.4	MANE Select	c.91-251A>G		intron	N/A	NP_066998.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAMP	ENST00000222304.5	TSL:1 MANE Select	c.91-251A>G		intron	N/A	ENSP00000222304.2
	HAMP	ENST00000593580.1	TSL:6	n.2022A>G		non_coding_transcript_exon	Exon 1 of 1
	HAMP	ENST00000598398.5	TSL:2	c.91-251A>G		intron	N/A	ENSP00000471894.1

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

African (AFR) AF: 0.231 AC: 2795 AN: 12104

American (AMR) AF: 0.525 AC: 9547 AN: 18196

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 7264 AN: 13228

East Asian (EAS) AF: 0.346 AC: 10371 AN: 29962

South Asian (SAS) AF: 0.514 AC: 22410 AN: 43628

European-Finnish (FIN) AF: 0.487 AC: 13552 AN: 27820

Middle Eastern (MID) AF: 0.512 AC: 954 AN: 1862

European-Non Finnish (NFE) AF: 0.528 AC: 136223 AN: 257774

Other (OTH) AF: 0.498 AC: 12461 AN: 25006

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

African (AFR) AF: 0.228 AC: 9442 AN: 41418

American (AMR) AF: 0.521 AC: 7946 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 1894 AN: 3472

East Asian (EAS) AF: 0.401 AC: 2074 AN: 5174

South Asian (SAS) AF: 0.505 AC: 2433 AN: 4814

European-Finnish (FIN) AF: 0.485 AC: 5092 AN: 10490

Middle Eastern (MID) AF: 0.555 AC: 162 AN: 292

European-Non Finnish (NFE) AF: 0.526 AC: 35753 AN: 67918

Other (OTH) AF: 0.466 AC: 985 AN: 2114

Alfa AF: 0.500 Hom.: 83293

Bravo AF: 0.428

Asia WGS AF: 0.478 AC: 1661 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.2
DANN	Benign	0.48
PhyloP100		0.080
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7251432; hg19: chr19-35775441;