chr6-26091108-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000410.4(HFE):c.340+4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 1,613,544 control chromosomes in the GnomAD database, including 106,933 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10495 hom., cov: 31)

Exomes 𝑓: 0.36 ( 96438 hom. )

Consequence

HFE
NM_000410.4 splice_region, intron

Scores

Splicing: ADA: 0.00003040

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -2.17

Publications

53 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:

HFE-AS1 (HGNC:55168): (HFE antisense RNA 1)

HFE-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 6-26091108-T-C is Benign according to our data. Variant chr6-26091108-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000410.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HFE	NM_000410.4	MANE Select	c.340+4T>C	splice_region intron	N/A	NP_000401.1	Q30201-1
HFE	NM_001384164.1		c.340+4T>C	splice_region intron	N/A	NP_001371093.1	H7C4K4
HFE	NM_001406751.1		c.340+4T>C	splice_region intron	N/A	NP_001393680.1	Q6B0J5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HFE	ENST00000357618.10	TSL:1 MANE Select	c.340+4T>C	splice_region intron	N/A	ENSP00000417404.1	Q30201-1
HFE	ENST00000470149.5	TSL:1	c.340+4T>C	splice_region intron	N/A	ENSP00000419725.1	Q6B0J5
HFE	ENST00000461397.6	TSL:1	c.340+4T>C	splice_region intron	N/A	ENSP00000420802.1	Q30201-3

Frequencies

GnomAD3 genomes

AF:

0.364

AC:

55358

AN:

151934

Hom.:

10487

Cov.:

show subpopulations

Gnomad AFR

AF:

0.378

Gnomad AMI

AF:

0.163

Gnomad AMR

AF:

0.405

Gnomad ASJ

AF:

0.341

Gnomad EAS

AF:

0.651

Gnomad SAS

AF:

0.365

Gnomad FIN

AF:

0.349

Gnomad MID

AF:

0.392

Gnomad NFE

AF:

0.329

Gnomad OTH

AF:

0.416

GnomAD2 exomes

AF:

0.375

AC:

94244

AN:

251046

AF XY:

0.373

show subpopulations

Gnomad AFR exome

AF:

0.375

Gnomad AMR exome

AF:

0.412

Gnomad ASJ exome

AF:

0.347

Gnomad EAS exome

AF:

0.673

Gnomad FIN exome

AF:

0.356

Gnomad NFE exome

AF:

0.324

Gnomad OTH exome

AF:

0.357

GnomAD4 exome

AF:

0.357

AC:

521118

AN:

1461492

Hom.:

96438

Cov.:

AF XY:

0.357

AC XY:

259272

AN XY:

727066

show subpopulations

African (AFR)

AF:

0.383

AC:

12834

AN:

33480

American (AMR)

AF:

0.413

AC:

18493

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.354

AC:

9252

AN:

26134

East Asian (EAS)

AF:

0.718

AC:

28509

AN:

39700

South Asian (SAS)

AF:

0.373

AC:

32133

AN:

86252

European-Finnish (FIN)

AF:

0.353

AC:

18866

AN:

53398

Middle Eastern (MID)

AF:

0.420

AC:

2420

AN:

5766

European-Non Finnish (NFE)

AF:

0.339

AC:

376925

AN:

1111658

Other (OTH)

AF:

0.359

AC:

21686

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

19316

38631

57947

77262

96578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12510

25020

37530

50040

62550

<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:

0.364

AC:

55397

AN:

152052

Hom.:

10495

Cov.:

AF XY:

0.370

AC XY:

27507

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.378

AC:

15696

AN:

41474

American (AMR)

AF:

0.406

AC:

6196

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.341

AC:

1185

AN:

3472

East Asian (EAS)

AF:

0.650

AC:

3351

AN:

5158

South Asian (SAS)

AF:

0.365

AC:

1761

AN:

4822

European-Finnish (FIN)

AF:

0.349

AC:

3690

AN:

10570

Middle Eastern (MID)

AF:

0.381

AC:

112

AN:

294

European-Non Finnish (NFE)

AF:

0.329

AC:

22380

AN:

67972

Other (OTH)

AF:

0.415

AC:

878

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1735

3471

5206

6942

8677

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

544

1088

1632

2176

2720

<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:

0.350

Hom.:

23609

Bravo

AF:

0.373

Asia WGS

AF:

0.454

AC:

1578

AN:

3478

EpiCase

AF:

0.340

EpiControl

AF:

0.331

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (3)

Hemochromatosis type 1 (2)

Hereditary hemochromatosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.10

(source)

DANN

Benign

0.76

PhyloP100

-2.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000030

dbscSNV1_RF

Benign

0.014

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over