rs140080192

chr6-26092897-G-Achr6-26092897-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000410.4(HFE):c.829G>A(p.Glu277Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,614,216 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (79 hom.)
• Consequence: HFE NM_000410.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.963

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 (MetaRNN=0.0042536557).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00146 (222/152334) while in subpopulation SAS AF= 0.0213 (103/4830). AF 95% confidence interval is 0.018. There are 5 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HFE	NM_000410.4	c.829G>A	p.Glu277Lys	missense_variant	4/6	ENST00000357618.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HFE	ENST00000357618.10	c.829G>A	p.Glu277Lys	missense_variant	4/6	1	NM_000410.4	P3

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152216 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00356 AC: 895 AN: 251412 Hom.: 29 AF XY: 0.00506 AC XY: 687 AN XY: 135890

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0256

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000554

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00215 AC: 3150 AN: 1461882 Hom.: 79 Cov.: 33 AF XY: 0.00306 AC XY: 2228 AN XY: 727246

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0266

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000521

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152334 Hom.: 5 Cov.: 31 AF XY: 0.00184 AC XY: 137 AN XY: 74482

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0213

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000733 Hom.: 3

Bravo AF: 0.000854

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00390 AC: 474

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	HFE: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2020	This variant is associated with the following publications: (PMID: 27153395, 27884173, 10612845, 22624560, 18762941) -

Hemochromatosis type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 03, 2016

The HFE c.829G>A (p.Glu277Lys) variant is a missense variant that has been reported in at least one study, in which it was found in a compound heterozygous state with a second missense variant in one Portuguese individual with suspected hereditary hemochromatosis (Mendes et al. 2009). Family studies showed that the individual's brother had the same genotype and high serum ferritin levels. Functional studies by Silva et al. (2012) suggest that the p.Glu277Lys variant affects splicing, protein cell surface presentation and protein processing. The p.Glu277Lys variant was absent from 50 controls (Bradbury et al. 2000) and is reported at a frequency of 0.02459 in the South Asian population of the Exome Aggregation Consortium. This allele frequency is high but is consistent with the disease prevalence, reduced penetrance and mild phenotype. The evidence for this variant is limited. The p.Glu277Lys variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for hereditary hemochromatosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Hereditary hemochromatosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0043	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.97	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.7	D;D;D;D;N;N;D;N;D;N
REVEL	Benign	0.16
Sift	Uncertain	0.025	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;D;D;D;D;D;D;D;.
Vest4		0.28
MVP		0.52
MPC		0.91
ClinPred		0.030	T
GERP RS		5.3
Varity_R		0.84
gMVP		0.54

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: rs140080192; hg19: chr6-26093125; COSMIC: COSV58512377; COSMIC: COSV58512377;