19-35284962-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM5PP3_ModerateBS1_Supporting

The NM_021175.4(HAMP):c.175C>G(p.Arg59Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,613,436 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

HAMP
NM_021175.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.168

Publications

7 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: Uncertain_significance. The variant received 3 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-35284963-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 917401.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.88

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000151 (23/152094) while in subpopulation NFE AF = 0.000309 (21/68020). AF 95% confidence interval is 0.000207. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAMP	NM_021175.4 link	c.175C>G	p.Arg59Gly	missense_variant	Exon 3 of 3	ENST00000222304.5	NP_066998.1	P81172

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HAMP	ENST00000222304.5 link	c.175C>G	p.Arg59Gly	missense_variant	Exon 3 of 3	1	NM_021175.4	ENSP00000222304.2	P81172
HAMP	ENST00000598398.5 link	c.175C>G	p.Arg59Gly	missense_variant	Exon 4 of 4	2		ENSP00000471894.1	P81172
HAMP	ENST00000593580.1 link	n.2446C>G		non_coding_transcript_exon_variant	Exon 1 of 1	6
ENSG00000307628	ENST00000827558.1 link	n.392-4089G>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000915

AC:

AN:

251488

AF XY:

0.0000883

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000308

AC:

450

AN:

1461342

Hom.:

Cov.:

AF XY:

0.000279

AC XY:

203

AN XY:

727020

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000391

AC:

435

AN:

1111504

Other (OTH)

AF:

0.000232

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000151

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41374

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000203

Hom.:

Bravo

AF:

0.000128

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 23, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HAMP c.175C>G (p.Arg59Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 251488 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in HAMP causing Hemochromatosis Type 2B (9.1e-05 vs 0.0011), allowing no conclusion about variant significance. c.175C>G has been reported in the literature as a variant in HAMP as a modifier gene that increases the phenotypic expression of the HFE p.C282Y homozygous genotype (Jacolot_2004) and has been subsequently reported with a non-informative genotype and an unclear association with primary iron overload (example, Santos_2011) with citations by others (example, Nemeth_2006, Castiella_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hemochromatosis Type 2B. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary hemochromatosis

Uncertain:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 59 of the HAMP protein (p.Arg59Gly). This variant is present in population databases (rs779021719, gnomAD 0.02%). This missense change has been observed in individual(s) with elevated iron indices and/or hemochromotosis (PMID: 14670915, 19787796, 21411349). ClinVar contains an entry for this variant (Variation ID: 241375). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hemochromatosis type 2B

Uncertain:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;D

Eigen

Benign

0.088

Eigen_PC

Benign

-0.043

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.74

.;T

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Uncertain

0.69

PhyloP100

0.17

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-5.8

.;D

REVEL

Pathogenic

0.65

Sift

Uncertain

0.021

.;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.60

MVP

0.96

MPC

0.96

ClinPred

0.69

GERP RS

2.2

Varity_R

0.60

gMVP

0.75

Mutation Taster

=68/32

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over