dbSNP rs1800758: HFE:c.892+48G>A (chr6-26093008-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.259

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 -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 rank	MANE	Protein	UniProt
HFE	NM_000410.4 link	c.892+48G>A		intron_variant	Intron 4 of 5	ENST00000357618.10	NP_000401.1	Q30201-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HFE	ENST00000357618.10 link	c.892+48G>A		intron_variant	Intron 4 of 5	1	NM_000410.4	ENSP00000417404.1		Q30201-1

Frequencies

GnomAD3 genomes

AF:

0.131

AC:

19932

AN:

152040

Hom.:

1367

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.129

AC XY:

93694

AN XY:

727038

show subpopulations

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.:

AF XY:

0.131

AC XY:

9759

AN XY:

74364

show subpopulations

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

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

HFE INTRONIC POLYMORPHISM

Benign:1

Nov 01, 1999

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

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