rs201587159

Variant names:

• chr19-35284855-G-A
• rs201587159
• NM_021175.4:c.150+7G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-35284855-G-A
• chr19-35284855-G-C
• chr19-35284855-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_021175.4(HAMP):​c.150+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,612,606 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: HAMP NM_021175.4 splice_region, intron
• Scores: Splicing: ADA: 0.000008682
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.41
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-35284855-G-A is Benign according to our data. Variant chr19-35284855-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 414002.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00106 (162/152210) while in subpopulation SAS AF = 0.00208 (10/4818). AF 95% confidence interval is 0.00113. There are 1 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAMP	NM_021175.4	c.150+7G>A		splice_region_variant, intron_variant	Intron 2 of 2	ENST00000222304.5	NP_066998.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAMP	ENST00000222304.5	c.150+7G>A		splice_region_variant, intron_variant	Intron 2 of 2	1	NM_021175.4	ENSP00000222304.2
HAMP	ENST00000593580.1	n.2339G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
HAMP	ENST00000598398.5	c.150+7G>A		splice_region_variant, intron_variant	Intron 3 of 3	2		ENSP00000471894.1
ENSG00000307628	ENST00000827558.1	n.392-3982C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152092 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000809

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00150 AC: 378 AN: 251416 AF XY: 0.00160

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000915

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00109 AC: 1598 AN: 1460396 Hom.: 4 Cov.: 30 AF XY: 0.00118 AC XY: 858 AN XY: 726610

African (AFR) AF: 0.0000598 AC: 2 AN: 33444

American (AMR) AF: 0.000425 AC: 19 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 482 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00183 AC: 158 AN: 86230

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5764

European-Non Finnish (NFE) AF: 0.000720 AC: 800 AN: 1110656

Other (OTH) AF: 0.00207 AC: 125 AN: 60348

GnomAD4 genome AF: 0.00106 AC: 162 AN: 152210 Hom.: 1 Cov.: 31 AF XY: 0.00118 AC XY: 88 AN XY: 74420

African (AFR) AF: 0.000241 AC: 10 AN: 41516

American (AMR) AF: 0.000981 AC: 15 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00208 AC: 10 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000809 AC: 55 AN: 68008

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00223 Hom.: 1

Bravo AF: 0.00108

EpiCase AF: 0.00115

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hemochromatosis type 2B Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary hemochromatosis Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.41
DANN	Benign	0.56
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000087
dbscSNV1_RF	Benign	0.0
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: rs201587159; hg19: chr19-35775758;