rs1800562

Variant names:

• chr6-26092913-G-A
• rs1800562
• NM_000410.4:c.845G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-26092913-G-A
• chr6-26092913-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PS3 PP3 PP5 BP4

The NM_000410.4(HFE):​c.845G>A​(p.Cys282Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.057 in 1,614,134 control chromosomes in the GnomAD database, including 3,399 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other,risk factor (no stars). ClinVar reports functional evidence for this variant: "SCV000461887: The c.845G>A variant affects HFE protein activity by preventing the formation of a disulfide bridge in the alpha-3 domain, which impairs the beta-2-microglobulin interaction and prevents the protein from reaching the cell surface (Feder et al. 1997" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.037 (151 hom., cov: 31)
  • Exomes 𝑓: 0.059 (3248 hom.)
• Consequence: HFE NM_000410.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity; other; risk factor criteria provided, conflicting classifications P:48 U:2 B:1 O:6
• Conservation: PhyloP100: 5.23
• Publications: 2922 publications found

Genes affected

HFE (HGNC:4886): (homeostatic iron regulator) The protein encoded by this gene is a membrane protein that is similar to MHC class I-type proteins and associates with beta2-microglobulin (beta2M). It is thought that this protein functions to regulate iron absorption by regulating the interaction of the transferrin receptor with transferrin. The iron storage disorder, hereditary haemochromatosis, is a recessive genetic disorder that results from defects in this gene. [provided by RefSeq, May 2022]

H2BC4 (HGNC:4757): (H2B clustered histone 4) Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. The protein has antibacterial and antifungal antimicrobial activity. The main transcript variant of this gene is intronless and encodes a replication-dependent histone that is a member of the histone H2B family. This transcript variant lacks a polyA tail but instead contains a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6. [provided by RefSeq, Apr 2020]

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000461887: The c.845G>A variant affects HFE protein activity by preventing the formation of a disulfide bridge in the alpha-3 domain, which impairs the beta-2-microglobulin interaction and prevents the protein from reaching the cell surface (Feder et al. 1997; Barton and Edwards 2018).; SCV001519562: "In-vitro experimental evidence suggests that the Cys282Tyr-mutant protein has impaired intracellular trafficking and accelerated degradation compared to wild-type HFE (e.g. Waheed_1997)"; SCV004177020: In vitro functional studies have shown that the variant causes reduced function (Ali-Rahmani F et al., PMID: 21243428; Boucherma R et al., PMID: 22531912; Levy JE et al., PMID: 10381492).; SCV004812520: In vitro functional assays with limited validation showed a significant impairment to protein trafficking and accelerated protein degradation indicating that this variant impacts protein function (PMID: 9162021, 9356458).; SCV005086593: "Functional analysis using transfected cell lines showed defects in HFE protein intracellular transport and cell surface expression (PMID: 9162021)."; SCV005382430: Experimental studies have shown that this missense change disrupts a disulfide bond in the Œ±3 domain of the HFE protein and impairs interaction of HFE with beta2-microglobulin, resulting in a block in intracellular transport and loss of cell surface expression of the Cys282Tyr variant protein (Waheed et. al., 1997).; SCV005415942: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV006583014: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 9162021, 9356458).; SCV000329362: Published functional studies demonstrate a damaging effect as C282Y results in a protein that does not reach the cell surface and is subject to accelerated degradation (PMID: 21243428, 9356458).; SCV001549492: Functional studies of the p.C282Y variant have demonstrated abnormal protein interaction, expression, processing and localization (Feder_1997_PMID:9162021; Waheed_1997_PMID:9356458).; SCV000219175: Experimental studies have shown that this missense change disrupts a disulfide bond in the α3 domain of the HFE protein and impairs interaction of HFE with beta2-microglobulin, resulting in a block in intracellular transport and loss of cell surface expression of the Cys282Tyr variant protein (PMID: 9162021, 9356458).; SCV002061285: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11040194; 23953397; 9162021; 9356458)"; SCV003702847: Functional studies have shown that this alteration leads to impaired intracellular transport of the protein and degradation before reaching the cell surface (Feder, 1997; Waheed, 1997).; SCV003920032: In vitro functional studies have shown that the mutant protein is retained in the ER and is unable to interact with beta2-microglobulin (Feder 1997 PMID:9162021, Waheed 1997 PMID:9356458).
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 6-26092913-G-A is Pathogenic according to our data. Variant chr6-26092913-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity|other|risk_factor. ClinVar VariationId is 9.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0073376894). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000410.4. 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
	HFE	NM_000410.4	MANE Select	c.845G>A	p.Cys282Tyr	missense	Exon 4 of 6	NP_000401.1	Q30201-1
	HFE	NM_001384164.1		c.845G>A	p.Cys282Tyr	missense	Exon 4 of 7	NP_001371093.1	H7C4K4
	HFE	NM_001406751.1		c.836G>A	p.Cys279Tyr	missense	Exon 5 of 7	NP_001393680.1	Q6B0J5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFE	ENST00000357618.10	TSL:1 MANE Select	c.845G>A	p.Cys282Tyr	missense	Exon 4 of 6	ENSP00000417404.1	Q30201-1
	HFE	ENST00000470149.5	TSL:1	c.836G>A	p.Cys279Tyr	missense	Exon 5 of 7	ENSP00000419725.1	Q6B0J5
	HFE	ENST00000461397.6	TSL:1	c.803G>A	p.Cys268Tyr	missense	Exon 4 of 6	ENSP00000420802.1	Q30201-3

Frequencies

GnomAD3 genomes AF: 0.0373 AC: 5679 AN: 152164 Hom.: 151 Cov.: 31

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.0356

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0647

Gnomad OTH AF: 0.0278

GnomAD2 exomes AF: 0.0332 AC: 8344 AN: 251236 AF XY: 0.0323

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0349

Gnomad NFE exome AF: 0.0574

Gnomad OTH exome AF: 0.0391

GnomAD4 exome AF: 0.0590 AC: 86298 AN: 1461852 Hom.: 3248 Cov.: 34 AF XY: 0.0568 AC XY: 41284 AN XY: 727228

African (AFR) AF: 0.00989 AC: 331 AN: 33478

American (AMR) AF: 0.0139 AC: 620 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 308 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.00214 AC: 185 AN: 86256

European-Finnish (FIN) AF: 0.0370 AC: 1979 AN: 53420

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5754

European-Non Finnish (NFE) AF: 0.0714 AC: 79409 AN: 1111990

Other (OTH) AF: 0.0571 AC: 3449 AN: 60394

GnomAD4 genome AF: 0.0373 AC: 5679 AN: 152282 Hom.: 151 Cov.: 31 AF XY: 0.0341 AC XY: 2539 AN XY: 74446

African (AFR) AF: 0.0110 AC: 459 AN: 41560

American (AMR) AF: 0.0186 AC: 284 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4832

European-Finnish (FIN) AF: 0.0356 AC: 378 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0647 AC: 4398 AN: 68010

Other (OTH) AF: 0.0275 AC: 58 AN: 2112

Alfa AF: 0.0522 Hom.: 1064

Bravo AF: 0.0348

TwinsUK AF: 0.0690 AC: 256

ALSPAC AF: 0.0794 AC: 306

ESP6500AA AF: 0.0152 AC: 67

ESP6500EA AF: 0.0641 AC: 551

ExAC AF: 0.0324 AC: 3937

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0569

EpiControl AF: 0.0502

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; other; risk factor

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
30	-	1	Hemochromatosis type 1 (32)
9	-	-	not provided (10)
2	-	-	Hereditary hemochromatosis (4)
2	-	-	HFE-related disorder (2)
1	-	-	Abdominal pain;C0004941:Atypical behavior;C0030193:Pain;C0031117:Peripheral neuropathy;C0497552:Abnormality of the nervous system;C4023819:Abnormality of the male genitalia;C4025831:Abnormal peripheral nervous system morphology (1)
1	-	-	Cardiomyopathy (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Inborn genetic diseases (1)
-	1	-	Neuroendocrine neoplasm (1)
-	1	-	Porphyrinuria;C0349506:Cutaneous photosensitivity (1)
1	-	-	Variegate porphyria;C0268323:Familial porphyria cutanea tarda;C1863052:Alzheimer disease type 1;C2673520:Microvascular complications of diabetes, susceptibility to, 7;C3280096:TRANSFERRIN SERUM LEVEL QUANTITATIVE TRAIT LOCUS 2;C3469186:Hemochromatosis type 1 (1)
-	-	-	Bronze diabetes (1)
-	-	-	Juvenile hemochromatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0073	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		5.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-8.9	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.82
MPC		1.1
ClinPred		0.090	T
GERP RS		5.3
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.92
Mutation Taster		=10/90	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1800562; hg19: chr6-26093141; COSMIC: COSV107360943; COSMIC: COSV107360943;