rs1572982

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000410.4(HFE):c.1007-47G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 1,580,402 control chromosomes in the GnomAD database, including 198,301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 21637 hom., cov: 31)

Exomes 𝑓: 0.49 ( 176664 hom. )

Consequence

HFE
NM_000410.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.29

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.03).

BP6

Variant 6-26094139-G-A is Benign according to our data. Variant chr6-26094139-G-A is described in ClinVar as [Benign]. Clinvar id is 1164200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HFE	NM_000410.4 linkuse as main transcript	c.1007-47G>A		intron_variant		ENST00000357618.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HFE	ENST00000357618.10 linkuse as main transcript	c.1007-47G>A		intron_variant		1	NM_000410.4	P3	Q30201-1

Frequencies

GnomAD3 genomes

AF:

0.526

AC:

79838

AN:

151786

Hom.:

21616

Cov.:

show subpopulations

Gnomad AFR

AF:

0.615

Gnomad AMI

AF:

0.302

Gnomad AMR

AF:

0.553

Gnomad ASJ

AF:

0.565

Gnomad EAS

AF:

0.713

Gnomad SAS

AF:

0.575

Gnomad FIN

AF:

0.451

Gnomad MID

AF:

0.589

Gnomad NFE

AF:

0.458

Gnomad OTH

AF:

0.579

GnomAD3 exomes

AF:

0.518

AC:

129403

AN:

249668

Hom.:

34540

AF XY:

0.520

AC XY:

70232

AN XY:

135140

show subpopulations

Gnomad AFR exome

AF:

0.618

Gnomad AMR exome

AF:

0.539

Gnomad ASJ exome

AF:

0.580

Gnomad EAS exome

AF:

0.715

Gnomad SAS exome

AF:

0.581

Gnomad FIN exome

AF:

0.455

Gnomad NFE exome

AF:

0.455

Gnomad OTH exome

AF:

0.510

GnomAD4 exome

AF:

0.492

AC:

703130

AN:

1428498

Hom.:

176664

Cov.:

AF XY:

0.495

AC XY:

352461

AN XY:

712736

show subpopulations

Gnomad4 AFR exome

AF:

0.624

Gnomad4 AMR exome

AF:

0.544

Gnomad4 ASJ exome

AF:

0.579

Gnomad4 EAS exome

AF:

0.789

Gnomad4 SAS exome

AF:

0.583

Gnomad4 FIN exome

AF:

0.456

Gnomad4 NFE exome

AF:

0.466

Gnomad4 OTH exome

AF:

0.510

GnomAD4 genome

AF:

0.526

AC:

79906

AN:

151904

Hom.:

21637

Cov.:

AF XY:

0.530

AC XY:

39371

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.616

Gnomad4 AMR

AF:

0.553

Gnomad4 ASJ

AF:

0.565

Gnomad4 EAS

AF:

0.712

Gnomad4 SAS

AF:

0.575

Gnomad4 FIN

AF:

0.451

Gnomad4 NFE

AF:

0.458

Gnomad4 OTH

AF:

0.575

Alfa

AF:

0.475

Hom.:

24906

Bravo

AF:

0.539

Asia WGS

AF:

0.588

AC:

2046

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary hemochromatosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Hemochromatosis type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2018

This variant is associated with the following publications: (PMID: 21412944) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

Cadd

Benign

0.0040

Dann

Benign

0.59

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