chr6-26096520-G-C

Variant names:

• chr6-26096520-G-C
• rs1045537
• NM_000410.4:c.*2294G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000410.4(HFE):​c.*2294G>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 0.0936 in 456,408 control chromosomes in the GnomAD database, including 2,388 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 0.11 (1031 hom., cov: 31)
  • Exomes 𝑓: 0.086 (1357 hom.)
• Consequence: HFE NM_000410.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.566
• Publications: 12 publications found

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFE	NM_000410.4	MANE Select	c.*2294G>C		3_prime_UTR	Exon 6 of 6	NP_000401.1
	HFE	NM_001384164.1		c.*2109G>C		3_prime_UTR	Exon 7 of 7	NP_001371093.1
	HFE	NM_001406751.1		c.*2294G>C		3_prime_UTR	Exon 7 of 7	NP_001393680.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFE	ENST00000357618.10	TSL:1 MANE Select	c.*2294G>C		3_prime_UTR	Exon 6 of 6	ENSP00000417404.1
	HFE	ENST00000714170.1		c.*2294G>C		3_prime_UTR	Exon 7 of 7	ENSP00000519459.1
	HFE	ENST00000714172.1		c.*2109G>C		3_prime_UTR	Exon 5 of 5	ENSP00000519461.1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16618 AN: 152120 Hom.: 1029 Cov.: 31

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0935

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.0188

Gnomad SAS AF: 0.0323

Gnomad FIN AF: 0.0478

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.114

GnomAD2 exomes AF: 0.0818 AC: 11192 AN: 136790 AF XY: 0.0808

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.0576

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.0188

Gnomad FIN exome AF: 0.0496

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.0919

GnomAD4 exome AF: 0.0857 AC: 26069 AN: 304170 Hom.: 1357 Cov.: 0 AF XY: 0.0815 AC XY: 14115 AN XY: 173222

African (AFR) AF: 0.162 AC: 1399 AN: 8618

American (AMR) AF: 0.0562 AC: 1533 AN: 27254

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 1365 AN: 10786

East Asian (EAS) AF: 0.0173 AC: 159 AN: 9210

South Asian (SAS) AF: 0.0457 AC: 2731 AN: 59732

European-Finnish (FIN) AF: 0.0519 AC: 664 AN: 12796

Middle Eastern (MID) AF: 0.126 AC: 348 AN: 2762

European-Non Finnish (NFE) AF: 0.104 AC: 16538 AN: 158786

Other (OTH) AF: 0.0936 AC: 1332 AN: 14226

GnomAD4 genome AF: 0.109 AC: 16635 AN: 152238 Hom.: 1031 Cov.: 31 AF XY: 0.105 AC XY: 7846 AN XY: 74438

African (AFR) AF: 0.162 AC: 6724 AN: 41528

American (AMR) AF: 0.0933 AC: 1425 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 400 AN: 3464

East Asian (EAS) AF: 0.0187 AC: 97 AN: 5190

South Asian (SAS) AF: 0.0323 AC: 156 AN: 4830

European-Finnish (FIN) AF: 0.0478 AC: 507 AN: 10614

Middle Eastern (MID) AF: 0.103 AC: 30 AN: 292

European-Non Finnish (NFE) AF: 0.104 AC: 7047 AN: 68018

Other (OTH) AF: 0.112 AC: 238 AN: 2116

Alfa AF: 0.110 Hom.: 217

Bravo AF: 0.115

Asia WGS AF: 0.0400 AC: 142 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.54
DANN	Benign	0.68
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1045537; hg19: chr6-26096748;