chr19-35284962-C-G

Position:

chr19-35284962-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

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 (★★).

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:2

Conservation

PhyloP100: 0.168

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAMP	NM_021175.4 linkuse as main transcript	c.175C>G	p.Arg59Gly	missense_variant	3/3	ENST00000222304.5	NP_066998.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
HAMP	ENST00000222304.5 linkuse as main transcript	c.175C>G	p.Arg59Gly	missense_variant	3/3	1	NM_021175.4	ENSP00000222304	P1
HAMP	ENST00000598398.5 linkuse as main transcript	c.175C>G	p.Arg59Gly	missense_variant	4/4	2		ENSP00000471894	P1
HAMP	ENST00000593580.1 linkuse as main transcript	n.2446C>G		non_coding_transcript_exon_variant	1/1

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

GnomAD3 exomes

AF:

0.0000915

AC:

AN:

251488

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135916

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000391

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000151

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

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:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 23, 2022

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 06, 2022

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). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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. -

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

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

MutationTaster

Benign

0.97

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over