rs140080192

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000410.4(HFE):c.829G>A(p.Glu277Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,614,216 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 5 hom., cov: 31)

Exomes 𝑓: 0.0022 ( 79 hom. )

Consequence

HFE
NM_000410.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.963

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042536557).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00146 (222/152334) while in subpopulation SAS AF= 0.0213 (103/4830). AF 95% confidence interval is 0.018. There are 5 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HFE	NM_000410.4 linkuse as main transcript	c.829G>A	p.Glu277Lys	missense_variant	4/6	ENST00000357618.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HFE	ENST00000357618.10 linkuse as main transcript	c.829G>A	p.Glu277Lys	missense_variant	4/6	1	NM_000410.4	P3	Q30201-1

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

218

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0205

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.00356

AC:

895

AN:

251412

Hom.:

AF XY:

0.00506

AC XY:

687

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0256

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000554

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00215

AC:

3150

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

2228

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00173

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.000574

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0266

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000521

Gnomad4 OTH exome

AF:

0.00142

GnomAD4 genome

AF:

0.00146

AC:

222

AN:

152334

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

137

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0213

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000733

Hom.:

Bravo

AF:

0.000854

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00390

AC:

474

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	HFE: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2020	This variant is associated with the following publications: (PMID: 27153395, 27884173, 10612845, 22624560, 18762941) -

Hemochromatosis type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 03, 2016

The HFE c.829G>A (p.Glu277Lys) variant is a missense variant that has been reported in at least one study, in which it was found in a compound heterozygous state with a second missense variant in one Portuguese individual with suspected hereditary hemochromatosis (Mendes et al. 2009). Family studies showed that the individual's brother had the same genotype and high serum ferritin levels. Functional studies by Silva et al. (2012) suggest that the p.Glu277Lys variant affects splicing, protein cell surface presentation and protein processing. The p.Glu277Lys variant was absent from 50 controls (Bradbury et al. 2000) and is reported at a frequency of 0.02459 in the South Asian population of the Exome Aggregation Consortium. This allele frequency is high but is consistent with the disease prevalence, reduced penetrance and mild phenotype. The evidence for this variant is limited. The p.Glu277Lys variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for hereditary hemochromatosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Hereditary hemochromatosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

.;.;.;.;T;T;.;.;.;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Benign

0.42

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0043

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

.;.;.;.;M;.;.;.;.;.

MutationTaster

Benign

0.97

D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.7

D;D;D;D;N;N;D;N;D;N

REVEL

Benign

0.16

Sift

Uncertain

0.025

D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0090

D;D;D;D;D;D;D;D;D;D

Polyphen

0.99

D;D;D;D;D;D;D;D;D;.

Vest4

0.28

MVP

0.52

MPC

0.91

ClinPred

0.030

GERP RS

5.3

Varity_R

0.84

gMVP

0.54

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over