6-26097156-T-C

Position:

• chr6-26097156-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000357618.10(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 ENST00000357618.10 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.74

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
HFE	NM_000410.4	c.*2930T>C		3_prime_UTR_variant	6/6	ENST00000357618.10	NP_000401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HFE	ENST00000357618.10	c.*2930T>C		3_prime_UTR_variant	6/6	1	NM_000410.4	ENSP00000417404	P3
H2BC4	ENST00000707188.1	c.*10-6122A>G		intron_variant, NMD_transcript_variant				ENSP00000516775

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66884 AN: 151946 Hom.: 16009 Cov.: 32

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: 94 AN: 216 Hom.: 23 Cov.: 0 AF XY: 0.433 AC XY: 52 AN XY: 120

Gnomad4 AFR exome AF: 1.00

Gnomad4 AMR exome AF: 0.333

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.417

Gnomad4 NFE exome AF: 0.446

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.440 AC: 66937 AN: 152064 Hom.: 16029 Cov.: 32 AF XY: 0.431 AC XY: 32024 AN XY: 74358

Gnomad4 AFR AF: 0.609

Gnomad4 AMR AF: 0.400

Gnomad4 ASJ AF: 0.524

Gnomad4 EAS AF: 0.152

Gnomad4 SAS AF: 0.377

Gnomad4 FIN AF: 0.248

Gnomad4 NFE AF: 0.399

Gnomad4 OTH AF: 0.484

Alfa AF: 0.405 Hom.: 16366

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
DANN	Benign	0.67

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

LitVar

Other links and lift over

dbSNP: rs6918586; hg19: chr6-26097384;