ENST00000707188.1:n.*1453T>G

Variant names:

• chr6-26087031-A-C
• rs62625313
• ENST00000707188.1:n.*1453T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000707188.1(H2BC4):​n.*1453T>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00988 in 152,322 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0099 (14 hom., cov: 32)
• Consequence: H2BC4 ENST00000707188.1 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00100
• Publications: 0 publications found

Genes affected

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)

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 Gene-Disease associations (from GenCC):

• hemochromatosis type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-26087031-A-C is Benign according to our data. Variant chr6-26087031-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 1204708.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00988 (1505/152322) while in subpopulation SAS AF = 0.0305 (147/4822). AF 95% confidence interval is 0.0265. There are 14 homozygotes in GnomAd4. There are 719 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HFE-AS1	NR_144383.1	n.1444T>G		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H2BC4	ENST00000707188.1	n.*1453T>G		non_coding_transcript_exon_variant	Exon 3 of 3			ENSP00000516775.1
H2BC4	ENST00000707188.1	n.*1453T>G		3_prime_UTR_variant	Exon 3 of 3			ENSP00000516775.1
HFE	ENST00000397022.7	c.-410A>C		upstream_gene_variant		1		ENSP00000380217.3

Frequencies

GnomAD3 genomes AF: 0.00989 AC: 1506 AN: 152204 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.0300

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00581

Gnomad OTH AF: 0.0124

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00988 AC: 1505 AN: 152322 Hom.: 14 Cov.: 32 AF XY: 0.00965 AC XY: 719 AN XY: 74498

African (AFR) AF: 0.0163 AC: 676 AN: 41564

American (AMR) AF: 0.00876 AC: 134 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3468

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5190

South Asian (SAS) AF: 0.0305 AC: 147 AN: 4822

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10622

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.00581 AC: 395 AN: 68032

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.00842 Hom.: 0

Bravo AF: 0.0108

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 16, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	8.0
DANN	Benign	0.80
PhyloP100		-0.0010
PromoterAI		-0.011	Neutral

Splicing

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

Other links and lift over

dbSNP: rs62625313; hg19: chr6-26087259;