6-26091041-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000410.4(HFE):​c.277G>T​(p.Gly93Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HFE
NM_000410.4 missense

Scores

6
6
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.655
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 made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HFENM_000410.4 linkc.277G>T p.Gly93Trp 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.277G>T p.Gly93Trp missense_variant Exon 2 of 6 1 NM_000410.4 ENSP00000417404.1 Q30201-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461814
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Benign
-0.015
T
BayesDel_noAF
Benign
-0.26
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.39
.;.;T;T;.;.;T
Eigen
Pathogenic
0.78
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.93
D;D;D;D;D;D;D
M_CAP
Benign
0.024
T
MetaRNN
Pathogenic
0.86
D;D;D;D;D;D;D
MetaSVM
Benign
-1.2
T
MutationAssessor
Pathogenic
3.7
.;H;H;.;H;H;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-3.8
D;D;D;D;D;D;D
REVEL
Benign
0.25
Sift
Pathogenic
0.0
D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D
Polyphen
1.0
D;D;D;D;D;D;.
Vest4
0.61
MutPred
0.85
.;Gain of catalytic residue at L91 (P = 0.0053);Gain of catalytic residue at L91 (P = 0.0053);Gain of catalytic residue at L91 (P = 0.0053);Gain of catalytic residue at L91 (P = 0.0053);Gain of catalytic residue at L91 (P = 0.0053);Gain of catalytic residue at L91 (P = 0.0053);
MVP
0.35
MPC
0.93
ClinPred
0.99
D
GERP RS
5.2
Varity_R
0.91
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-26091269; API