rs150121265

Positions:

• chr19-35285039-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_021175.4(HAMP):​c.252G>A​(p.Thr84=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,602,518 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: HAMP NM_021175.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -5.61

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-35285039-G-A is Benign according to our data. Variant chr19-35285039-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219770.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-5.61 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAMP	NM_021175.4	c.252G>A	p.Thr84=	synonymous_variant	3/3	ENST00000222304.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAMP	ENST00000222304.5	c.252G>A	p.Thr84=	synonymous_variant	3/3	1	NM_021175.4	P1
HAMP	ENST00000598398.5	c.252G>A	p.Thr84=	synonymous_variant	4/4	2		P1
HAMP	ENST00000593580.1	n.2523G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000946 AC: 144 AN: 152158 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000795 AC: 200 AN: 251472 Hom.: 0 AF XY: 0.000853 AC XY: 116 AN XY: 135912

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000867

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: 0.00167

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00143 AC: 2073 AN: 1450240 Hom.: 2 Cov.: 28 AF XY: 0.00136 AC XY: 981 AN XY: 722402

Gnomad4 AFR exome AF: 0.000210

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00183

Gnomad4 OTH exome AF: 0.000584

GnomAD4 genome AF: 0.000946 AC: 144 AN: 152278 Hom.: 0 Cov.: 31 AF XY: 0.000873 AC XY: 65 AN XY: 74464

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00181

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00134 Hom.: 0

Bravo AF: 0.000929

EpiCase AF: 0.00147

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hemochromatosis type 2B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Hereditary hemochromatosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.058
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs150121265; hg19: chr19-35775942; COSMIC: COSV55885861;