6-26087508-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

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).

• Frequency:
  • Genomes: 𝑓 0.00043 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (3 hom.)
• Consequence: HFE NM_000410.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.520

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-AS1 (HGNC:):

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

Verdict is Benign. Variant got -11 ACMG points.

• PM1: In a region_of_interest Alpha-1 (size 91) in uniprot entity HFE_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_000410.4
• 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 GnomAd at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HFE	NM_000410.4	c.68G>A	p.Arg23His	missense_variant	1/6	ENST00000357618.10
HFE-AS1	NR_144383.1	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	c.68G>A	p.Arg23His	missense_variant	1/6	1	NM_000410.4	P3

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152206 Hom.: 2 Cov.: 32

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.: 1 AF XY: 0.000673 AC XY: 91 AN XY: 135274

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.: 3 Cov.: 30 AF XY: 0.000730 AC XY: 530 AN XY: 726454

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: 65 AN: 152324 Hom.: 2 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74484

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.: 0

Bravo AF: 0.000283

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000585 AC: 71

EpiCase AF: 0.000764

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign: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	Sep 01, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; 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

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.090
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.87	D;T;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.0097	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.35	T
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	T
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	T
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

Other links and lift over

dbSNP: rs148161858; hg19: chr6-26087736;