6-26093798-G-T

Variant names:

• chr6-26093798-G-T
• rs2858996
• NM_000410.4:c.1007-388G>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.1007-388G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 151,878 control chromosomes in the GnomAD database, including 2,658 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 0.18 (2658 hom., cov: 31)
• Consequence: HFE NM_000410.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.54
• 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.22 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFE	NM_000410.4	MANE Select	c.1007-388G>T		intron	N/A	NP_000401.1
	HFE	NM_001384164.1		c.1007-388G>T		intron	N/A	NP_001371093.1
	HFE	NM_001406751.1		c.998-388G>T		intron	N/A	NP_001393680.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFE	ENST00000357618.10	TSL:1 MANE Select	c.1007-388G>T		intron	N/A	ENSP00000417404.1
	HFE	ENST00000470149.5	TSL:1	c.998-388G>T		intron	N/A	ENSP00000419725.1
	HFE	ENST00000461397.6	TSL:1	c.965-388G>T		intron	N/A	ENSP00000420802.1

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26673 AN: 151760 Hom.: 2658 Cov.: 31

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.346

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.0792

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.155

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

GnomAD4 genome AF: 0.176 AC: 26676 AN: 151878 Hom.: 2658 Cov.: 31 AF XY: 0.171 AC XY: 12682 AN XY: 74230

African (AFR) AF: 0.117 AC: 4837 AN: 41418

American (AMR) AF: 0.137 AC: 2089 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 435 AN: 3468

East Asian (EAS) AF: 0.151 AC: 776 AN: 5148

South Asian (SAS) AF: 0.0786 AC: 379 AN: 4820

European-Finnish (FIN) AF: 0.220 AC: 2317 AN: 10516

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15175 AN: 67940

Other (OTH) AF: 0.156 AC: 329 AN: 2110

Alfa AF: 0.194 Hom.: 4453

Bravo AF: 0.170

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.052
DANN	Benign	0.51
PhyloP100		-1.5
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: rs2858996; hg19: chr6-26094026;