dbSNP rs8101606: HAMP:c.90+986A>C (chr19-35283653-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0730

Publications

9 publications found

Variant links:

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

HAMP links:

ENSG00000307628 (HGNC:):

ENSG00000307628 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
HAMP	NM_021175.4 link	c.90+986A>C		intron_variant	Intron 1 of 2	ENST00000222304.5	NP_066998.1	P81172

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HAMP	ENST00000222304.5 link	c.90+986A>C	intron_variant	Intron 1 of 2	1	NM_021175.4	ENSP00000222304.2	P81172
HAMP	ENST00000593580.1 link	n.1137A>C	non_coding_transcript_exon_variant	Exon 1 of 1	6
HAMP	ENST00000598398.5 link	c.90+986A>C	intron_variant	Intron 2 of 3	2		ENSP00000471894.1	P81172
ENSG00000307628	ENST00000827558.1 link	n.392-2780T>G	intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.203

AC:

30805

AN:

152014

Hom.:

3352

Cov.:

show subpopulations

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:

AN:

188

Hom.:

Cov.:

AF XY:

0.158

AC XY:

AN XY:

114

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.125

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.180

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.170

AC:

AN:

106

Other (OTH)

AF:

0.200

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.546

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.203

AC:

30808

AN:

152132

Hom.:

3347

Cov.:

AF XY:

0.203

AC XY:

15065

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.165

AC:

6857

AN:

41520

American (AMR)

AF:

0.169

AC:

2589

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.190

AC:

658

AN:

3466

East Asian (EAS)

AF:

0.0168

AC:

AN:

5178

South Asian (SAS)

AF:

0.218

AC:

1051

AN:

4818

European-Finnish (FIN)

AF:

0.267

AC:

2818

AN:

10564

Middle Eastern (MID)

AF:

0.238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.235

AC:

15945

AN:

67976

Other (OTH)

AF:

0.227

AC:

478

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1207

2415

3622

4830

6037

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

334

668

1002

1336

1670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.192

Hom.:

1453

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

(source)

DANN

Benign

0.36

PhyloP100

0.073

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over