rs1045537

Positions:

• chr6-26096520-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000410.4(HFE):​c.*2294G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0936 in 456,408 control chromosomes in the GnomAD database, including 2,388 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 (1031 hom., cov: 31)
  • Exomes 𝑓: 0.086 (1357 hom.)
• Consequence: HFE NM_000410.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.566

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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HFE	NM_000410.4	c.*2294G>C		3_prime_UTR_variant	6/6	ENST00000357618.10	NP_000401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HFE	ENST00000357618.10	c.*2294G>C		3_prime_UTR_variant	6/6	1	NM_000410.4	ENSP00000417404.1
H2BC4	ENST00000707188.1	n.*10-5486C>G		intron_variant				ENSP00000516775.1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16618 AN: 152120 Hom.: 1029 Cov.: 31

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0935

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.0188

Gnomad SAS AF: 0.0323

Gnomad FIN AF: 0.0478

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.114

GnomAD3 exomes AF: 0.0818 AC: 11192 AN: 136790 Hom.: 577 AF XY: 0.0808 AC XY: 6004 AN XY: 74348

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.0576

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.0188

Gnomad SAS exome AF: 0.0463

Gnomad FIN exome AF: 0.0496

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.0919

GnomAD4 exome AF: 0.0857 AC: 26069 AN: 304170 Hom.: 1357 Cov.: 0 AF XY: 0.0815 AC XY: 14115 AN XY: 173222

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.0562

Gnomad4 ASJ exome AF: 0.127

Gnomad4 EAS exome AF: 0.0173

Gnomad4 SAS exome AF: 0.0457

Gnomad4 FIN exome AF: 0.0519

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.0936

GnomAD4 genome AF: 0.109 AC: 16635 AN: 152238 Hom.: 1031 Cov.: 31 AF XY: 0.105 AC XY: 7846 AN XY: 74438

Gnomad4 AFR AF: 0.162

Gnomad4 AMR AF: 0.0933

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.0187

Gnomad4 SAS AF: 0.0323

Gnomad4 FIN AF: 0.0478

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.112

Alfa AF: 0.110 Hom.: 217

Bravo AF: 0.115

Asia WGS AF: 0.0400 AC: 142 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.54
DANN	Benign	0.68

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: rs1045537; hg19: chr6-26096748;