Genetic Variant HFE:c.*2930T>C (chr6-26097156-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000410.4(HFE):c.*2930T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 152,280 control chromosomes in the GnomAD database, including 16,052 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.44 ( 16029 hom., cov: 32)

Exomes 𝑓: 0.44 ( 23 hom. )

Consequence

HFE
NM_000410.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.74

Publications

27 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]

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HFE	NM_000410.4 link	c.*2930T>C		3_prime_UTR_variant	Exon 6 of 6	ENST00000357618.10	NP_000401.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
HFE	ENST00000357618.10 link	c.*2930T>C	3_prime_UTR_variant	Exon 6 of 6	1	NM_000410.4	ENSP00000417404.1
HFE	ENST00000714172.1 link	c.*2745T>C	3_prime_UTR_variant	Exon 5 of 5			ENSP00000519461.1
HFE	ENST00000714164.1 link	c.*2930T>C	3_prime_UTR_variant	Exon 2 of 2			ENSP00000519453.1
H2BC4	ENST00000707188.1 link	n.*10-6122A>G	intron_variant	Intron 1 of 2			ENSP00000516775.1

Frequencies

GnomAD3 genomes

AF:

0.440

AC:

66884

AN:

151946

Hom.:

16009

Cov.:

show subpopulations

Gnomad AFR

AF:

0.609

Gnomad AMI

AF:

0.263

Gnomad AMR

AF:

0.400

Gnomad ASJ

AF:

0.524

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.377

Gnomad FIN

AF:

0.248

Gnomad MID

AF:

0.503

Gnomad NFE

AF:

0.399

Gnomad OTH

AF:

0.490

GnomAD4 exome

AF:

0.435

AC:

AN:

216

Hom.:

Cov.:

AF XY:

0.433

AC XY:

AN XY:

120

show subpopulations

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AF:

0.333

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.417

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.446

AC:

AN:

186

Other (OTH)

AF:

0.250

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.440

AC:

66937

AN:

152064

Hom.:

16029

Cov.:

AF XY:

0.431

AC XY:

32024

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.609

AC:

25257

AN:

41450

American (AMR)

AF:

0.400

AC:

6110

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.524

AC:

1815

AN:

3466

East Asian (EAS)

AF:

0.152

AC:

786

AN:

5176

South Asian (SAS)

AF:

0.377

AC:

1821

AN:

4828

European-Finnish (FIN)

AF:

0.248

AC:

2622

AN:

10582

Middle Eastern (MID)

AF:

0.503

AC:

148

AN:

294

European-Non Finnish (NFE)

AF:

0.399

AC:

27118

AN:

67966

Other (OTH)

AF:

0.484

AC:

1021

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1816

3632

5449

7265

9081

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

600

1200

1800

2400

3000

<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:

0.413

Hom.:

21823

Bravo

AF:

0.460

Asia WGS

AF:

0.287

AC:

1000

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.0

(source)

DANN

Benign

0.67

PhyloP100

-2.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over