rs146776859

Variant names:

• chr19-35284790-C-T
• rs146776859
• NM_021175.4:c.92C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_021175.4(HAMP):​c.92C>T​(p.Thr31Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,613,058 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T31T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0026 (12 hom.)
• Consequence: HAMP NM_021175.4 missense, splice_region
• Scores: Splicing: ADA: 0.0002571
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.749
• Publications: 3 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• hemochromatosis type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000307628 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062108934).
• BP6: Variant 19-35284790-C-T is Benign according to our data. Variant chr19-35284790-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216876.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00302 (460/152168) while in subpopulation NFE AF = 0.00341 (232/67992). AF 95% confidence interval is 0.00305. There are 2 homozygotes in GnomAd4. There are 285 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAMP	NM_021175.4	MANE Select	c.92C>T	p.Thr31Met	missense splice_region	Exon 2 of 3	NP_066998.1	P81172

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAMP	ENST00000222304.5	TSL:1 MANE Select	c.92C>T	p.Thr31Met	missense splice_region	Exon 2 of 3	ENSP00000222304.2	P81172
	HAMP	ENST00000598398.5	TSL:2	c.92C>T	p.Thr31Met	missense splice_region	Exon 3 of 4	ENSP00000471894.1	P81172
	HAMP	ENST00000869749.1		c.92C>T	p.Thr31Met	missense splice_region	Exon 2 of 3	ENSP00000539808.1

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 461 AN: 152050 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0185

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00341

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00331 AC: 832 AN: 251358 AF XY: 0.00329

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0177

Gnomad NFE exome AF: 0.00363

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00257 AC: 3760 AN: 1460890 Hom.: 12 Cov.: 31 AF XY: 0.00251 AC XY: 1823 AN XY: 726838

African (AFR) AF: 0.000478 AC: 16 AN: 33456

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86244

European-Finnish (FIN) AF: 0.0160 AC: 857 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00247 AC: 2741 AN: 1111090

Other (OTH) AF: 0.00214 AC: 129 AN: 60358

GnomAD4 genome AF: 0.00302 AC: 460 AN: 152168 Hom.: 2 Cov.: 31 AF XY: 0.00383 AC XY: 285 AN XY: 74390

African (AFR) AF: 0.000626 AC: 26 AN: 41522

American (AMR) AF: 0.000262 AC: 4 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.0185 AC: 196 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00341 AC: 232 AN: 67992

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00260 Hom.: 2

Bravo AF: 0.00161

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00339 AC: 412

EpiCase AF: 0.00202

EpiControl AF: 0.00273

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Hemochromatosis type 2B (1)
-	-	1	Hereditary hemochromatosis (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	14
DANN	Benign	0.73
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.036
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.64	T
PhyloP100		0.75
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.25
Sift	Benign	0.24	T
Sift4G	Benign	0.17	T
Polyphen		0.72	P
Vest4		0.17
MVP		0.91
MPC		0.25
ClinPred		0.014	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.044
gMVP		0.51
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00026
dbscSNV1_RF	Benign	0.012
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

Other links and lift over

dbSNP: rs146776859; hg19: chr19-35775693; COSMIC: COSV106092776; COSMIC: COSV106092776;