6-26088870-C-T

Variant names:

• chr6-26088870-C-T
• rs9366637
• NM_000410.4:c.76+1354C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000410.4(HFE):​c.76+1354C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 151,970 control chromosomes in the GnomAD database, including 1,582 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1582 hom., cov: 30)
• Consequence: HFE NM_000410.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.193
• Publications: 19 publications found

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]

HFE-AS1 (HGNC:55168): (HFE antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.509 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000410.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFE	NM_000410.4	MANE Select	c.76+1354C>T		intron	N/A	NP_000401.1	Q30201-1
	HFE	NM_001384164.1		c.76+1354C>T		intron	N/A	NP_001371093.1	H7C4K4
	HFE	NM_001406751.1		c.76+1354C>T		intron	N/A	NP_001393680.1	Q6B0J5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFE	ENST00000357618.10	TSL:1 MANE Select	c.76+1354C>T		intron	N/A	ENSP00000417404.1	Q30201-1
	HFE	ENST00000470149.5	TSL:1	c.76+1354C>T		intron	N/A	ENSP00000419725.1	Q6B0J5
	HFE	ENST00000461397.6	TSL:1	c.76+1354C>T		intron	N/A	ENSP00000420802.1	Q30201-3

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16329 AN: 151852 Hom.: 1575 Cov.: 30

Gnomad AFR AF: 0.0942

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.0891

Gnomad EAS AF: 0.525

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0590

Gnomad OTH AF: 0.127

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.108 AC: 16349 AN: 151970 Hom.: 1582 Cov.: 30 AF XY: 0.117 AC XY: 8671 AN XY: 74256

African (AFR) AF: 0.0942 AC: 3903 AN: 41442

American (AMR) AF: 0.197 AC: 2998 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.0891 AC: 309 AN: 3468

East Asian (EAS) AF: 0.525 AC: 2716 AN: 5172

South Asian (SAS) AF: 0.189 AC: 910 AN: 4804

European-Finnish (FIN) AF: 0.110 AC: 1157 AN: 10536

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0590 AC: 4013 AN: 67988

Other (OTH) AF: 0.129 AC: 272 AN: 2110

Alfa AF: 0.0833 Hom.: 4389

Bravo AF: 0.114

Asia WGS AF: 0.306 AC: 1060 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.2
DANN	Benign	0.72
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9366637; hg19: chr6-26089098;