chr6-26096818-T-C

Variant names:

• chr6-26096818-T-C
• rs12346
• NM_000410.4:c.*2592T>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.*2592T>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 0.721 in 355,102 control chromosomes in the GnomAD database, including 93,669 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 0.76 (44333 hom., cov: 33)
  • Exomes 𝑓: 0.69 (49336 hom.)
• Consequence: HFE NM_000410.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.20
• Publications: 9 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HFE	NM_000410.4	c.*2592T>C		3_prime_UTR_variant	Exon 6 of 6	ENST00000357618.10	NP_000401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HFE	ENST00000357618.10	c.*2592T>C		3_prime_UTR_variant	Exon 6 of 6	1	NM_000410.4	ENSP00000417404.1

Frequencies

GnomAD3 genomes AF: 0.756 AC: 114897 AN: 152054 Hom.: 44290 Cov.: 33

Gnomad AFR AF: 0.914

Gnomad AMI AF: 0.652

Gnomad AMR AF: 0.715

Gnomad ASJ AF: 0.693

Gnomad EAS AF: 0.865

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.777

GnomAD4 exome AF: 0.694 AC: 140918 AN: 202930 Hom.: 49336 Cov.: 0 AF XY: 0.691 AC XY: 78115 AN XY: 112972

African (AFR) AF: 0.924 AC: 4892 AN: 5296

American (AMR) AF: 0.699 AC: 7081 AN: 10124

Ashkenazi Jewish (ASJ) AF: 0.707 AC: 3165 AN: 4478

East Asian (EAS) AF: 0.870 AC: 7276 AN: 8364

South Asian (SAS) AF: 0.668 AC: 27090 AN: 40542

European-Finnish (FIN) AF: 0.667 AC: 5799 AN: 8690

Middle Eastern (MID) AF: 0.753 AC: 521 AN: 692

European-Non Finnish (NFE) AF: 0.680 AC: 78225 AN: 114966

Other (OTH) AF: 0.702 AC: 6869 AN: 9778

GnomAD4 genome AF: 0.756 AC: 114995 AN: 152172 Hom.: 44333 Cov.: 33 AF XY: 0.754 AC XY: 56063 AN XY: 74378

African (AFR) AF: 0.914 AC: 37988 AN: 41558

American (AMR) AF: 0.715 AC: 10929 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 2401 AN: 3464

East Asian (EAS) AF: 0.864 AC: 4469 AN: 5170

South Asian (SAS) AF: 0.655 AC: 3163 AN: 4828

European-Finnish (FIN) AF: 0.672 AC: 7101 AN: 10568

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.684 AC: 46507 AN: 67974

Other (OTH) AF: 0.774 AC: 1638 AN: 2116

Alfa AF: 0.731 Hom.: 14187

Bravo AF: 0.769

Asia WGS AF: 0.734 AC: 2549 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.59
DANN	Benign	0.59
PhyloP100		-1.2
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: rs12346; hg19: chr6-26097046;