rs707889

Positions:

• chr6-26095703-G-A
• chr6-26095703-G-T

Variant summary

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

The NM_000410.4(HFE):​c.*1477G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 151,964 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 (3728 hom., cov: 31)
  • Exomes 𝑓: 0.38 (1 hom.)
• Consequence: HFE NM_000410.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.108

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=-0.65).
• 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/exons	MANE	UniProt
HFE	NM_000410.4	c.*1477G>A		3_prime_UTR_variant	6/6	ENST00000357618.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HFE	ENST00000357618.10	c.*1477G>A		3_prime_UTR_variant	6/6	1	NM_000410.4	P3
H2BC4	ENST00000707188.1	c.*10-4669C>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32485 AN: 151828 Hom.: 3722 Cov.: 31

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.0802

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.188

GnomAD4 exome AF: 0.375 AC: 6 AN: 16 Hom.: 1 Cov.: 0 AF XY: 0.667 AC XY: 4 AN XY: 6

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 1.00

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.200

GnomAD4 genome AF: 0.214 AC: 32513 AN: 151948 Hom.: 3728 Cov.: 31 AF XY: 0.208 AC XY: 15437 AN XY: 74292

Gnomad4 AFR AF: 0.245

Gnomad4 AMR AF: 0.155

Gnomad4 ASJ AF: 0.128

Gnomad4 EAS AF: 0.151

Gnomad4 SAS AF: 0.0792

Gnomad4 FIN AF: 0.220

Gnomad4 NFE AF: 0.225

Gnomad4 OTH AF: 0.188

Alfa AF: 0.199 Hom.: 4386

Bravo AF: 0.212

Asia WGS AF: 0.145 AC: 505 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.1
DANN	Benign	0.61

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: rs707889; hg19: chr6-26095931;