rs807209

Positions:

• chr6-26092637-C-G
• chr6-26092637-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The ENST00000470149.5(HFE):​c.645C>G​(p.Gly215=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0082 in 1,614,010 control chromosomes in the GnomAD database, including 721 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.038 (388 hom., cov: 31)
  • Exomes 𝑓: 0.0051 (333 hom.)
• Consequence: HFE ENST00000470149.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.226

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-26092637-C-G is Benign according to our data. Variant chr6-26092637-C-G is described in ClinVar as [Benign]. Clinvar id is 1292203.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.226 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HFE	NM_000410.4	c.617-48C>G		intron_variant		ENST00000357618.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HFE	ENST00000357618.10	c.617-48C>G		intron_variant		1	NM_000410.4	P3

Frequencies

GnomAD3 genomes AF: 0.0381 AC: 5789 AN: 152106 Hom.: 383 Cov.: 31

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.0326

GnomAD3 exomes AF: 0.0111 AC: 2771 AN: 250314 Hom.: 145 AF XY: 0.00844 AC XY: 1142 AN XY: 135378

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00223

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.0000927

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.00766

GnomAD4 exome AF: 0.00508 AC: 7424 AN: 1461786 Hom.: 333 Cov.: 33 AF XY: 0.00457 AC XY: 3323 AN XY: 727196

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.00272

Gnomad4 EAS exome AF: 0.00108

Gnomad4 SAS exome AF: 0.000985

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00140

Gnomad4 OTH exome AF: 0.0100

GnomAD4 genome AF: 0.0382 AC: 5814 AN: 152224 Hom.: 388 Cov.: 31 AF XY: 0.0369 AC XY: 2749 AN XY: 74418

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.0182

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00198

Gnomad4 OTH AF: 0.0322

Alfa AF: 0.00219 Hom.: 1

Bravo AF: 0.0442

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.7
DANN	Benign	0.65

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: rs807209; hg19: chr6-26092865;