6-26093798-G-T

Variant names:

• chr6-26093798-G-T
• rs2858996
• NM_000410.4:c.1007-388G>T

Variant summary

Our verdict is Benign. Variant got -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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HFE	NM_000410.4	c.1007-388G>T		intron_variant	Intron 5 of 5	ENST00000357618.10	NP_000401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HFE	ENST00000357618.10	c.1007-388G>T		intron_variant	Intron 5 of 5	1	NM_000410.4	ENSP00000417404.1

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

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.151

Gnomad4 SAS AF: 0.0786

Gnomad4 FIN AF: 0.220

Gnomad4 NFE AF: 0.223

Gnomad4 OTH AF: 0.156

Alfa AF: 0.195 Hom.: 3003

Bravo AF: 0.170

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.052
DANN	Benign	0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs2858996; hg19: chr6-26094026;