rs17596719

Variant names:

• chr6-26096966-G-A
• rs17596719
• NM_000410.4:c.*2740G>A

Variant summary

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

The NM_000410.4(HFE):​c.*2740G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 212,730 control chromosomes in the GnomAD database, including 1,498 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 0.094 (878 hom., cov: 33)
  • Exomes 𝑓: 0.12 (620 hom.)
• Consequence: HFE NM_000410.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.979

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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HFE	NM_000410.4	c.*2740G>A		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.*2740G>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_000410.4	ENSP00000417404.1
H2BC4	ENST00000707188.1	n.*10-5932C>T		intron_variant	Intron 1 of 2			ENSP00000516775.1

Frequencies

GnomAD3 genomes AF: 0.0946 AC: 14374 AN: 152012 Hom.: 879 Cov.: 33

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.0634

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.103

GnomAD4 exome AF: 0.123 AC: 7464 AN: 60600 Hom.: 620 Cov.: 0 AF XY: 0.132 AC XY: 4343 AN XY: 32982

Gnomad4 AFR exome AF: 0.0213

Gnomad4 AMR exome AF: 0.0977

Gnomad4 ASJ exome AF: 0.182

Gnomad4 EAS exome AF: 0.0569

Gnomad4 SAS exome AF: 0.190

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.108

Gnomad4 OTH exome AF: 0.119

GnomAD4 genome AF: 0.0944 AC: 14363 AN: 152130 Hom.: 878 Cov.: 33 AF XY: 0.0958 AC XY: 7130 AN XY: 74390

Gnomad4 AFR AF: 0.0284

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.195

Gnomad4 EAS AF: 0.0636

Gnomad4 SAS AF: 0.204

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.101

Alfa AF: 0.120 Hom.: 1698

Bravo AF: 0.0881

Asia WGS AF: 0.118 AC: 413 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.62

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: rs17596719; hg19: chr6-26097194;