ENST00000707188.1:n.*10-7493G>A

Variant names:

• chr6-26098527-C-T
• rs1150658
• ENST00000707188.1:n.*10-7493G>A

Variant summary

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

The ENST00000707188.1(H2BC4):​n.*10-7493G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 151,896 control chromosomes in the GnomAD database, including 3,729 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 0.21 (3729 hom., cov: 32)
• Consequence: H2BC4 ENST00000707188.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.958
• Publications: 10 publications found

Genes affected

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 (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]

HFE Gene-Disease associations (from GenCC):

• hemochromatosis type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HFE	NM_000410.4	c.*4301C>T		downstream_gene_variant		ENST00000357618.10	NP_000401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H2BC4	ENST00000707188.1	n.*10-7493G>A		intron_variant	Intron 1 of 2			ENSP00000516775.1
HFE	ENST00000357618.10	c.*4301C>T		downstream_gene_variant		1	NM_000410.4	ENSP00000417404.1
HFE	ENST00000714164.1	c.*4301C>T		downstream_gene_variant				ENSP00000519453.1

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32501 AN: 151776 Hom.: 3723 Cov.: 32

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.0812

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.187

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

GnomAD4 genome AF: 0.214 AC: 32529 AN: 151896 Hom.: 3729 Cov.: 32 AF XY: 0.208 AC XY: 15447 AN XY: 74232

African (AFR) AF: 0.245 AC: 10154 AN: 41388

American (AMR) AF: 0.155 AC: 2364 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 446 AN: 3466

East Asian (EAS) AF: 0.152 AC: 785 AN: 5172

South Asian (SAS) AF: 0.0802 AC: 386 AN: 4812

European-Finnish (FIN) AF: 0.221 AC: 2327 AN: 10530

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15320 AN: 67962

Other (OTH) AF: 0.188 AC: 396 AN: 2108

Alfa AF: 0.216 Hom.: 14142

Bravo AF: 0.213

Asia WGS AF: 0.145 AC: 506 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.4
DANN	Benign	0.65
PhyloP100		-0.96

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1150658; hg19: chr6-26098755;