ENST00000486147.1:n.783G>A

Variant names:

• chr6-26093008-G-A
• rs1800758
• ENST00000486147.1:n.783G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000486147.1(HFE):​n.783G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,613,608 control chromosomes in the GnomAD database, including 13,973 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1368 hom., cov: 31)
  • Exomes 𝑓: 0.13 (12605 hom.)
• Consequence: HFE ENST00000486147.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.259
• Publications: 14 publications found

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 6-26093008-G-A is Benign according to our data. Variant chr6-26093008-G-A is described in ClinVar as Benign. ClinVar VariationId is 14.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000486147.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFE	NM_000410.4	MANE Select	c.892+48G>A		intron	N/A	NP_000401.1
	HFE	NM_001384164.1		c.892+48G>A		intron	N/A	NP_001371093.1
	HFE	NM_001406751.1		c.883+48G>A		intron	N/A	NP_001393680.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFE	ENST00000486147.1	TSL:1	n.783G>A		non_coding_transcript_exon	Exon 3 of 5
	HFE	ENST00000357618.10	TSL:1 MANE Select	c.892+48G>A		intron	N/A	ENSP00000417404.1
	HFE	ENST00000470149.5	TSL:1	c.883+48G>A		intron	N/A	ENSP00000419725.1

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19932 AN: 152040 Hom.: 1367 Cov.: 31

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.0638

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.134

GnomAD2 exomes AF: 0.132 AC: 33142 AN: 250950 AF XY: 0.137

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.219

Gnomad EAS exome AF: 0.0429

Gnomad FIN exome AF: 0.100

Gnomad NFE exome AF: 0.125

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.126 AC: 183977 AN: 1461450 Hom.: 12605 Cov.: 35 AF XY: 0.129 AC XY: 93694 AN XY: 727038

African (AFR) AF: 0.140 AC: 4694 AN: 33472

American (AMR) AF: 0.120 AC: 5375 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 5464 AN: 26134

East Asian (EAS) AF: 0.0707 AC: 2806 AN: 39696

South Asian (SAS) AF: 0.210 AC: 18105 AN: 86212

European-Finnish (FIN) AF: 0.103 AC: 5489 AN: 53418

Middle Eastern (MID) AF: 0.193 AC: 1083 AN: 5598

European-Non Finnish (NFE) AF: 0.119 AC: 132575 AN: 1111830

Other (OTH) AF: 0.139 AC: 8386 AN: 60370

GnomAD4 genome AF: 0.131 AC: 19938 AN: 152158 Hom.: 1368 Cov.: 31 AF XY: 0.131 AC XY: 9759 AN XY: 74364

African (AFR) AF: 0.145 AC: 6024 AN: 41490

American (AMR) AF: 0.131 AC: 1999 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 732 AN: 3468

East Asian (EAS) AF: 0.0639 AC: 331 AN: 5178

South Asian (SAS) AF: 0.209 AC: 1007 AN: 4822

European-Finnish (FIN) AF: 0.101 AC: 1069 AN: 10594

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8314 AN: 68006

Other (OTH) AF: 0.132 AC: 278 AN: 2112

Alfa AF: 0.133 Hom.: 1047

Bravo AF: 0.131

Asia WGS AF: 0.125 AC: 437 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HFE INTRONIC POLYMORPHISM Benign:1

Nov 01, 1999

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.79
DANN	Benign	0.72
PhyloP100		-0.26
PromoterAI		-0.014	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1800758; hg19: chr6-26093236; COSMIC: COSV58512489; COSMIC: COSV58512489;