chr6-26091108-T-C

Variant names:

• chr6-26091108-T-C
• rs2071303
• NM_000410.4:c.340+4T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000410.4(HFE):​c.340+4T>C variant causes a splice 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.00003040
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.17

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 -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 rank	MANE	Protein	UniProt
HFE	NM_000410.4	c.340+4T>C		splice_region_variant, intron_variant	Intron 2 of 5	ENST00000357618.10	NP_000401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HFE	ENST00000357618.10	c.340+4T>C		splice_region_variant, intron_variant	Intron 2 of 5	1	NM_000410.4	ENSP00000417404.1

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55358 AN: 151934 Hom.: 10487 Cov.: 31

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

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.: 41 AF XY: 0.357 AC XY: 259272 AN XY: 727066

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.: 31 AF XY: 0.370 AC XY: 27507 AN XY: 74320

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Dec 01, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Oct 14, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Sep 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25262004, 10401000, 26799139, 26501199) -

Oct 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hemochromatosis type 1 Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary hemochromatosis Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Other links and lift over

dbSNP: rs2071303; hg19: chr6-26091336; COSMIC: COSV58512737; COSMIC: COSV58512737;