chr6-26091475-G-C

Position:

chr6-26091475-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000410.4(HFE):c.502G>C(p.Glu168Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000647 in 1,614,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00067 ( 0 hom. )

Consequence

HFE
NM_000410.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 2.32

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:

HFE (HGNC:):

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.052369863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HFE	NM_000410.4 linkuse as main transcript	c.502G>C	p.Glu168Gln	missense_variant	3/6	ENST00000357618.10	NP_000401.1	Q30201-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HFE	ENST00000357618.10 linkuse as main transcript	c.502G>C	p.Glu168Gln	missense_variant	3/6	1	NM_000410.4	ENSP00000417404.1		Q30201-1

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000446

AC:

112

AN:

251276

Hom.:

AF XY:

0.000508

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00129

Gnomad NFE exome

AF:

0.000686

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000666

AC:

974

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000630

AC XY:

458

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00110

Gnomad4 NFE exome

AF:

0.000782

Gnomad4 OTH exome

AF:

0.000563

GnomAD4 genome

AF:

0.000460

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00169

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000610

Hom.:

Bravo

AF:

0.000246

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000387

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hemochromatosis type 1

Uncertain:4

Uncertain significance, criteria provided, single submitter	research	Center for Precision Medicine, Vanderbilt University Medical Center	Mar 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 18, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2024	Identified in individuals with hereditary hemochromatosis; however, all reported individuals also harbored other variants in the HFE gene and it remains unclear whether this variant is sufficient to cause disease (PMID: 10953950, 12537660, 12681966, 15477198, 19214108, 19787796); Identified in a patient with hyperferritinemia and analyses suggested this variant was in cis with the p.(His63Asp) variant (PMID: 29084376); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12870733, 12681966, 15477198, 12537660, 12952143, 15025725, 19214108, 19787796, 29590070, 34426522, 10953950, 19759876, 29084376) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	HFE: PM2, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 29, 2022	BP4 -

Hereditary hemochromatosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 168 of the HFE protein (p.Glu168Gln). This variant is present in population databases (rs146519482, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hemochromatosis (PMID: 10953950, 12681966, 15025725, 15477198, 19214108, 19787796). ClinVar contains an entry for this variant (Variation ID: 222651). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

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

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.0064

MetaRNN

Benign

0.052

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

.;.;L;.;L;.;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.53

N;N;N;N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.030

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

Sift4G

Benign

0.13

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

Polyphen

0.99

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

Vest4

0.36

MVP

0.28

MPC

0.85

ClinPred

0.066

GERP RS

2.5

Varity_R

0.47

gMVP

0.77

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