6-26088662-T-G

Variant names:

• chr6-26088662-T-G
• rs2794719
• NM_000410.4:c.76+1146T>G

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+1146T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 152,052 control chromosomes in the GnomAD database, including 11,369 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 0.37 (11369 hom., cov: 32)
• Consequence: HFE NM_000410.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.227
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HFE	NM_000410.4	c.76+1146T>G		intron_variant	Intron 1 of 5	ENST00000357618.10	NP_000401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HFE	ENST00000357618.10	c.76+1146T>G		intron_variant	Intron 1 of 5	1	NM_000410.4	ENSP00000417404.1

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56600 AN: 151934 Hom.: 11366 Cov.: 32

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.472

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.708

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.379

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

GnomAD4 genome AF: 0.372 AC: 56618 AN: 152052 Hom.: 11369 Cov.: 32 AF XY: 0.377 AC XY: 28020 AN XY: 74328

African (AFR) AF: 0.239 AC: 9924 AN: 41460

American (AMR) AF: 0.413 AC: 6310 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1092 AN: 3462

East Asian (EAS) AF: 0.708 AC: 3661 AN: 5174

South Asian (SAS) AF: 0.370 AC: 1780 AN: 4816

European-Finnish (FIN) AF: 0.436 AC: 4608 AN: 10572

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.411 AC: 27930 AN: 67974

Other (OTH) AF: 0.381 AC: 806 AN: 2114

Alfa AF: 0.389 Hom.: 21684

Bravo AF: 0.367

Asia WGS AF: 0.516 AC: 1794 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.8
DANN	Benign	0.55
PhyloP100		-0.23
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: rs2794719; hg19: chr6-26088890;