Genetic Variant HFE:p.Gly215Gly (chr6-26092637-C-G) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_001406751.1(HFE):c.645C>G(p.Gly215Gly) 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
NM_001406751.1 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.226

Variant links:

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]

HFE links:

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]

H2BC4 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
HFE	NM_000410.4 link	c.617-48C>G		intron_variant	Intron 3 of 5	ENST00000357618.10	NP_000401.1	Q30201-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HFE	ENST00000357618.10 link	c.617-48C>G		intron_variant	Intron 3 of 5	1	NM_000410.4	ENSP00000417404.1		Q30201-1

Frequencies

GnomAD3 genomes

AF:

0.0381

AC:

5789

AN:

152106

Hom.:

383

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.00457

AC XY:

3323

AN XY:

727196

show subpopulations

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.:

AF XY:

0.0369

AC XY:

2749

AN XY:

74418

show subpopulations

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.:

Bravo

AF:

0.0442

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.00196

EpiControl

AF:

0.00237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over