rs1800758

chr6-26093008-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000410.4(HFE):c.892+48G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,613,608 control chromosomes in the GnomAD database, including 13,973 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1368 hom., cov: 31)
  • Exomes 𝑓: 0.13 (12605 hom.)
• Consequence: HFE NM_000410.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.259

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]

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 6-26093008-G-A is Benign according to our data. Variant chr6-26093008-G-A is described in ClinVar as [Benign]. Clinvar id is 14.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-26093008-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HFE	NM_000410.4	c.892+48G>A		intron_variant		ENST00000357618.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HFE	ENST00000357618.10	c.892+48G>A		intron_variant		1	NM_000410.4	P3

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19932 AN: 152040 Hom.: 1367 Cov.: 31

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.0638

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.134

GnomAD3 exomes AF: 0.132 AC: 33142 AN: 250950 Hom.: 2594 AF XY: 0.137 AC XY: 18621 AN XY: 135692

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.219

Gnomad EAS exome AF: 0.0429

Gnomad SAS exome AF: 0.209

Gnomad FIN exome AF: 0.100

Gnomad NFE exome AF: 0.125

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.126 AC: 183977 AN: 1461450 Hom.: 12605 Cov.: 35 AF XY: 0.129 AC XY: 93694 AN XY: 727038

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.120

Gnomad4 ASJ exome AF: 0.209

Gnomad4 EAS exome AF: 0.0707

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.103

Gnomad4 NFE exome AF: 0.119

Gnomad4 OTH exome AF: 0.139

GnomAD4 genome AF: 0.131 AC: 19938 AN: 152158 Hom.: 1368 Cov.: 31 AF XY: 0.131 AC XY: 9759 AN XY: 74364

Gnomad4 AFR AF: 0.145

Gnomad4 AMR AF: 0.131

Gnomad4 ASJ AF: 0.211

Gnomad4 EAS AF: 0.0639

Gnomad4 SAS AF: 0.209

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.132

Alfa AF: 0.134 Hom.: 588

Bravo AF: 0.131

Asia WGS AF: 0.125 AC: 437 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 11, 2018

- -

HFE INTRONIC POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Nov 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.79
Dann	Benign	0.72

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

LitVar

Other links and lift over

dbSNP: rs1800758; hg19: chr6-26093236; COSMIC: COSV58512489; COSMIC: COSV58512489;