6-26087508-G-A

Position:

chr6-26087508-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000410.4(HFE):c.68G>A(p.Arg23His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000631 in 1,612,782 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R23L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00043 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00065 ( 3 hom. )

Consequence

HFE
NM_000410.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.520

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-AS1 (HGNC:):

HFE-AS1 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0096851885).

BP6

Variant 6-26087508-G-A is Benign according to our data. Variant chr6-26087508-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 356194.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000427 (65/152324) while in subpopulation SAS AF= 0.0029 (14/4832). AF 95% confidence interval is 0.00175. There are 2 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HFE	NM_000410.4 linkuse as main transcript	c.68G>A	p.Arg23His	missense_variant	1/6	ENST00000357618.10
HFE-AS1	NR_144383.1 linkuse as main transcript	n.967C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HFE	ENST00000357618.10 linkuse as main transcript	c.68G>A	p.Arg23His	missense_variant	1/6	1	NM_000410.4	P3	Q30201-1

Frequencies

GnomAD3 genomes

AF:

0.000427

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00289

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000573

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000569

AC:

142

AN:

249394

Hom.:

AF XY:

0.000673

AC XY:

AN XY:

135274

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000999

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.00206

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.000586

Gnomad OTH exome

AF:

0.000494

GnomAD4 exome

AF:

0.000652

AC:

952

AN:

1460458

Hom.:

Cov.:

AF XY:

0.000730

AC XY:

530

AN XY:

726454

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00205

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.000601

Gnomad4 OTH exome

AF:

0.00129

GnomAD4 genome

AF:

0.000427

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000573

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000587

Hom.:

Bravo

AF:

0.000283

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000585

AC:

EpiCase

AF:

0.000764

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	HFE: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2024	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26582918) -

Hemochromatosis type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary hemochromatosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

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

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.87

D;T;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.0097

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

MetaSVM

Benign

-0.35

MutationAssessor

Benign

0.29

N;N;N;N;N;N;.;N;N;N;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.3

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

REVEL

Benign

0.051

Sift

Uncertain

0.0010

D;D;D;T;T;D;D;D;D;T;D

Sift4G

Uncertain

0.013

D;T;D;T;D;T;T;D;T;T;T

Polyphen

1.0

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

Vest4

0.36

MVP

0.77

MPC

0.95

ClinPred

0.079

GERP RS

2.9

Varity_R

0.053

gMVP

0.55

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