rs104894696

Variant names:

• chr19-35284999-G-A
• rs104894696
• NM_021175.4:c.212G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_021175.4(HAMP):​c.212G>A​(p.Gly71Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,614,026 control chromosomes in the GnomAD database, including 5 homozygotes. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0027 (4 hom.)
• Consequence: HAMP NM_021175.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.210
• Publications: 26 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 -16 ACMG points.

• BP6: Variant 19-35284999-G-A is Benign according to our data. Variant chr19-35284999-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 4286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00183 (278/152294) while in subpopulation NFE AF = 0.00319 (217/68010). AF 95% confidence interval is 0.00284. There are 1 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.212G>A	p.Gly71Asp	missense	Exon 3 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.212G>A	p.Gly71Asp	missense	Exon 3 of 3	ENSP00000222304.2	P81172
	HAMP	ENST00000598398.5	TSL:2	c.212G>A	p.Gly71Asp	missense	Exon 4 of 4	ENSP00000471894.1	P81172
	HAMP	ENST00000869749.1		c.200G>A	p.Gly67Asp	missense	Exon 3 of 3	ENSP00000539808.1

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 278 AN: 152176 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00168 AC: 422 AN: 251490 AF XY: 0.00158

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00270 AC: 3949 AN: 1461732 Hom.: 4 Cov.: 31 AF XY: 0.00256 AC XY: 1859 AN XY: 727184

African (AFR) AF: 0.000329 AC: 11 AN: 33476

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

Ashkenazi Jewish (ASJ) AF: 0.00593 AC: 155 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.000468 AC: 25 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00325 AC: 3609 AN: 1111862

Other (OTH) AF: 0.00227 AC: 137 AN: 60394

GnomAD4 genome AF: 0.00183 AC: 278 AN: 152294 Hom.: 1 Cov.: 31 AF XY: 0.00160 AC XY: 119 AN XY: 74474

African (AFR) AF: 0.000457 AC: 19 AN: 41556

American (AMR) AF: 0.000785 AC: 12 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00319 AC: 217 AN: 68010

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

Alfa AF: 0.00249 Hom.: 1

Bravo AF: 0.00175

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00203 AC: 246

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00261

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	HAMP-related disorder (1)
-	-	1	Hemochromatosis type 1 (1)
-	-	1	Hemochromatosis type 2B (1)
-	-	1	Hereditary hemochromatosis (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	-	Hemochromatosis, type 2a, modifier of (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	0.71
DANN	Benign	0.91
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.34	T
PhyloP100		-0.21
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.57
Sift	Benign	0.23	T
Sift4G	Benign	0.17	T
Polyphen		0.44	B
Vest4		0.74
MVP		0.81
MPC		0.37
ClinPred		0.0090	T
GERP RS		-4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.29
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs104894696; hg19: chr19-35775902; COSMIC: COSV107292523;