ENST00000470149:c.-48C>G

Variant names:

• chr6-26087393-C-G
• rs41266793
• ENST00000470149:c.-48C>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000470149(HFE):​c.-48C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000844 in 1,598,408 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (5 hom.)
• Consequence: HFE ENST00000470149 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.31

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]

HFE-AS1 (HGNC:55168): (HFE antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-26087393-C-G is Benign according to our data. Variant chr6-26087393-C-G is described in ClinVar as [Benign]. Clinvar id is 906711.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000843 (1219/1446164) while in subpopulation MID AF= 0.00535 (29/5424). AF 95% confidence interval is 0.00382. There are 5 homozygotes in gnomad4_exome. There are 656 alleles in male gnomad4_exome subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HFE	NM_000410.4	c.-48C>G		upstream_gene_variant		ENST00000357618.10	NP_000401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HFE	ENST00000357618.10	c.-48C>G		upstream_gene_variant		1	NM_000410.4	ENSP00000417404.1

Frequencies

GnomAD3 genomes AF: 0.000855 AC: 130 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.000967

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00115 AC: 286 AN: 249156 Hom.: 1 AF XY: 0.00113 AC XY: 153 AN XY: 135398

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00670

Gnomad EAS exome AF: 0.000327

Gnomad SAS exome AF: 0.00173

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000933

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.000843 AC: 1219 AN: 1446164 Hom.: 5 Cov.: 27 AF XY: 0.000911 AC XY: 656 AN XY: 720452

Gnomad4 AFR exome AF: 0.0000604

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00587

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.00175

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000646

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.000854 AC: 130 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000887 AC XY: 66 AN XY: 74444

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.000969

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000979

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hemochromatosis type 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.82
DANN	Benign	0.38

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: rs41266793; hg19: chr6-26087621;