dbSNP rs1800562: HFE:p.Cys282Tyr (chr6-26092913-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PP3PP5BP4BS1_SupportingBS2

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).

Frequency

Genomes: 𝑓 0.037 ( 151 hom., cov: 31)

Exomes 𝑓: 0.059 ( 3248 hom. )

Consequence

HFE
NM_000410.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; other; risk factor criteria provided, conflicting classifications P:48U:2B:1O:6

Conservation

PhyloP100: 5.23

Publications

2886 publications found

Variant links:

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]

HFE links:

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]

H2BC4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

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.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0373 (5679/152282) while in subpopulation NFE AF = 0.0647 (4398/68010). AF 95% confidence interval is 0.0631. There are 151 homozygotes in GnomAd4. There are 2539 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 151 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HFE	NM_000410.4	MANE Select	c.845G>A	p.Cys282Tyr	missense	Exon 4 of 6	NP_000401.1
HFE	NM_001384164.1		c.845G>A	p.Cys282Tyr	missense	Exon 4 of 7	NP_001371093.1
HFE	NM_001406751.1		c.836G>A	p.Cys279Tyr	missense	Exon 5 of 7	NP_001393680.1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.0373

AC:

5679

AN:

152164

Hom.:

151

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0568

AC XY:

41284

AN XY:

727228

show subpopulations

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:

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:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0714

AC:

79409

AN:

1111990

Other (OTH)

AF:

0.0571

AC:

3449

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

4610

9220

13830

18440

23050

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2980

5960

8940

11920

14900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0373

AC:

5679

AN:

152282

Hom.:

151

Cov.:

AF XY:

0.0341

AC XY:

2539

AN XY:

74446

show subpopulations

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:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.00228

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0356

AC:

378

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0647

AC:

4398

AN:

68010

Other (OTH)

AF:

0.0275

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

289

578

868

1157

1446

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:

ESP6500EA

AF:

0.0641

AC:

551

ExAC

AF:

0.0324

AC:

3937

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0569

EpiControl

AF:

0.0502

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity; other; risk factor

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hemochromatosis type 1 (32)

not provided (10)

Hereditary hemochromatosis (4)

HFE-related disorder (2)

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)

Cardiomyopathy (1)

Hereditary cancer-predisposing syndrome (1)

Inborn genetic diseases (1)

Neuroendocrine neoplasm (1)

Porphyrinuria;C0349506:Cutaneous photosensitivity (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

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0073

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

PhyloP100

5.2

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-8.9

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.82

MPC

1.1

ClinPred

0.090

GERP RS

5.3

PromoterAI

-0.021

Neutral

(source)

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)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over