19-35284953-C-T

Variant names:

• chr19-35284953-C-T
• rs104894695
• NM_021175.4:c.166C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_021175.4(HAMP):​c.166C>T​(p.Arg56*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: HAMP NM_021175.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.873
• Publications: 5 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-35284953-C-T is Pathogenic according to our data. Variant chr19-35284953-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 4284.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021175.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAMP	NM_021175.4	MANE Select	c.166C>T	p.Arg56*	stop_gained	Exon 3 of 3	NP_066998.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAMP	ENST00000222304.5	TSL:1 MANE Select	c.166C>T	p.Arg56*	stop_gained	Exon 3 of 3	ENSP00000222304.2
	HAMP	ENST00000598398.5	TSL:2	c.166C>T	p.Arg56*	stop_gained	Exon 4 of 4	ENSP00000471894.1
	HAMP	ENST00000869749.1		c.154C>T	p.Arg52*	stop_gained	Exon 3 of 3	ENSP00000539808.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461140 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726980

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111326

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hemochromatosis type 2B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Benign	-0.023
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.096	N
PhyloP100		0.87
Vest4		0.80
GERP RS		0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=27/173	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894695; hg19: chr19-35775856; COSMIC: COSV55885498;