rs111033557

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000410.4(HFE):​c.175G>A​(p.Val59Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

HFE
NM_000410.4 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2B:1

Conservation

PhyloP100: 2.16

Publications

16 publications found
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]
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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HFENM_000410.4 linkc.175G>A p.Val59Met missense_variant Exon 2 of 6 ENST00000357618.10 NP_000401.1 Q30201-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HFEENST00000357618.10 linkc.175G>A p.Val59Met missense_variant Exon 2 of 6 1 NM_000410.4 ENSP00000417404.1 Q30201-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152122
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000278
AC:
7
AN:
251490
AF XY:
0.0000368
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000439
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000342
AC:
50
AN:
1461880
Hom.:
0
Cov.:
32
AF XY:
0.0000344
AC XY:
25
AN XY:
727236
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33480
American (AMR)
AF:
0.0000447
AC:
2
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.0000423
AC:
47
AN:
1112006
Other (OTH)
AF:
0.00
AC:
0
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.485
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152122
Hom.:
0
Cov.:
30
AF XY:
0.0000404
AC XY:
3
AN XY:
74306
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41414
American (AMR)
AF:
0.00
AC:
0
AN:
15270
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10600
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
68022
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.458
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000681
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 04, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: HFE c.175G>A (p.Val59Met) results in a conservative amino acid change located in the MHC class I-like antigen recognition-like domain (IPR011161) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251490 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. In a cross-sectional review, c.175G>A has been reported in the literature as a non-informative genotype in a Caucasian control cohort (de Villiers_1999) or unclear reporting on detection despite inclusion within HFE gene mutation panels (example, Costa-Matos_2013, Sangiuolo_2015, Castiella_2016, Turkmen_2017, Schneeweiss-Gleixner_2021). These report(s) do not provide unequivocal conclusions about a penetrant association of the variant with Hemochromatosis Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26547814, 23657305, 25504993, 33791166, 28111930, 10401000). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hemochromatosis type 1 Uncertain:1
May 28, 2019
Mendelics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

HFE POLYMORPHISM Benign:1
Aug 01, 1999
OMIM
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Benign
-0.082
T
BayesDel_noAF
Benign
-0.18
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.19
.;.;T;T;.;.;T
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Benign
0.39
N
LIST_S2
Uncertain
0.94
D;D;D;D;D;D;D
M_CAP
Benign
0.021
T
MetaRNN
Uncertain
0.67
D;D;D;D;D;D;D
MetaSVM
Benign
-0.96
T
MutationAssessor
Uncertain
2.6
.;M;M;.;M;M;.
PhyloP100
2.2
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-2.1
N;N;N;N;N;N;N
REVEL
Benign
0.27
Sift
Pathogenic
0.0
D;D;D;D;D;D;D
Sift4G
Uncertain
0.049
D;D;T;T;D;T;T
Polyphen
1.0
D;D;D;D;D;D;.
Vest4
0.63
MutPred
0.87
.;Loss of phosphorylation at Y61 (P = 0.0985);Loss of phosphorylation at Y61 (P = 0.0985);Loss of phosphorylation at Y61 (P = 0.0985);Loss of phosphorylation at Y61 (P = 0.0985);Loss of phosphorylation at Y61 (P = 0.0985);Loss of phosphorylation at Y61 (P = 0.0985);
MVP
0.20
MPC
0.85
ClinPred
0.52
D
GERP RS
3.5
Varity_R
0.53
gMVP
0.89
Mutation Taster
=0/100
disease causing

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

Other links and lift over

dbSNP: rs111033557; hg19: chr6-26091167; COSMIC: COSV100352608; COSMIC: COSV100352608; API