6-26091108-T-C

Variant summary

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

The NM_000410.4(HFE):c.340+4T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 1,613,544 control chromosomes in the GnomAD database, including 106,933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10495 hom., cov: 31)

Exomes 𝑓: 0.36 ( 96438 hom. )

Consequence

HFE
NM_000410.4 splice_donor_region, intron

Scores

Splicing: ADA: 0.00003040

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -2.17

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 6-26091108-T-C is Benign according to our data. Variant chr6-26091108-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 129225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-26091108-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.631 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.340+4T>C		splice_donor_region_variant, intron_variant		ENST00000357618.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HFE	ENST00000357618.10 linkuse as main transcript	c.340+4T>C		splice_donor_region_variant, intron_variant		1	NM_000410.4	P3	Q30201-1

Frequencies

GnomAD3 genomes

AF:

0.364

AC:

55358

AN:

151934

Hom.:

10487

Cov.:

show subpopulations

Gnomad AFR

AF:

0.378

Gnomad AMI

AF:

0.163

Gnomad AMR

AF:

0.405

Gnomad ASJ

AF:

0.341

Gnomad EAS

AF:

0.651

Gnomad SAS

AF:

0.365

Gnomad FIN

AF:

0.349

Gnomad MID

AF:

0.392

Gnomad NFE

AF:

0.329

Gnomad OTH

AF:

0.416

GnomAD3 exomes

AF:

0.375

AC:

94244

AN:

251046

Hom.:

18914

AF XY:

0.373

AC XY:

50687

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.375

Gnomad AMR exome

AF:

0.412

Gnomad ASJ exome

AF:

0.347

Gnomad EAS exome

AF:

0.673

Gnomad SAS exome

AF:

0.371

Gnomad FIN exome

AF:

0.356

Gnomad NFE exome

AF:

0.324

Gnomad OTH exome

AF:

0.357

GnomAD4 exome

AF:

0.357

AC:

521118

AN:

1461492

Hom.:

96438

Cov.:

AF XY:

0.357

AC XY:

259272

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.383

Gnomad4 AMR exome

AF:

0.413

Gnomad4 ASJ exome

AF:

0.354

Gnomad4 EAS exome

AF:

0.718

Gnomad4 SAS exome

AF:

0.373

Gnomad4 FIN exome

AF:

0.353

Gnomad4 NFE exome

AF:

0.339

Gnomad4 OTH exome

AF:

0.359

GnomAD4 genome

AF:

0.364

AC:

55397

AN:

152052

Hom.:

10495

Cov.:

AF XY:

0.370

AC XY:

27507

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.378

Gnomad4 AMR

AF:

0.406

Gnomad4 ASJ

AF:

0.341

Gnomad4 EAS

AF:

0.650

Gnomad4 SAS

AF:

0.365

Gnomad4 FIN

AF:

0.349

Gnomad4 NFE

AF:

0.329

Gnomad4 OTH

AF:

0.415

Alfa

AF:

0.344

Hom.:

13262

Bravo

AF:

0.373

Asia WGS

AF:

0.454

AC:

1578

AN:

3478

EpiCase

AF:

0.340

EpiControl

AF:

0.331

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 01, 2016	c.340+4T>C in intron 2 of HFE: This variant is not expected to have clinical sig nificance because it has been identified in 37.4% (105403/282154) of total chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org/; dbSNP rs2071303). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hemochromatosis type 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2018	This variant is associated with the following publications: (PMID: 25262004, 10401000, 26799139, 26501199) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -

Hereditary hemochromatosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

Cadd

Benign

0.10

Dann

Benign

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000030

dbscSNV1_RF

Benign

0.014

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