rs17596719

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 20 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.194 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFE	NM_000410.4	MANE Select	c.*2740G>A		3_prime_UTR	Exon 6 of 6	NP_000401.1	Q30201-1
	HFE	NM_001384164.1		c.*2555G>A		3_prime_UTR	Exon 7 of 7	NP_001371093.1	H7C4K4
	HFE	NM_001406751.1		c.*2740G>A		3_prime_UTR	Exon 7 of 7	NP_001393680.1	Q6B0J5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFE	ENST00000357618.10	TSL:1 MANE Select	c.*2740G>A		3_prime_UTR	Exon 6 of 6	ENSP00000417404.1	Q30201-1
	HFE	ENST00000714172.1		c.*2555G>A		3_prime_UTR	Exon 5 of 5	ENSP00000519461.1	A0AAQ5BHL2
	HFE	ENST00000714164.1		c.*2740G>A		3_prime_UTR	Exon 2 of 2	ENSP00000519453.1	A0AAQ5BHM2

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

African (AFR) AF: 0.0213 AC: 11 AN: 516

American (AMR) AF: 0.0977 AC: 239 AN: 2446

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 231 AN: 1266

East Asian (EAS) AF: 0.0569 AC: 87 AN: 1528

South Asian (SAS) AF: 0.190 AC: 2228 AN: 11740

European-Finnish (FIN) AF: 0.102 AC: 347 AN: 3416

Middle Eastern (MID) AF: 0.211 AC: 41 AN: 194

European-Non Finnish (NFE) AF: 0.108 AC: 3924 AN: 36500

Other (OTH) AF: 0.119 AC: 356 AN: 2994

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

African (AFR) AF: 0.0284 AC: 1177 AN: 41516

American (AMR) AF: 0.106 AC: 1622 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 677 AN: 3470

East Asian (EAS) AF: 0.0636 AC: 329 AN: 5174

South Asian (SAS) AF: 0.204 AC: 986 AN: 4824

European-Finnish (FIN) AF: 0.102 AC: 1074 AN: 10568

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8105 AN: 67982

Other (OTH) AF: 0.101 AC: 214 AN: 2112

Alfa AF: 0.110 Hom.: 2598

Bravo AF: 0.0881

Asia WGS AF: 0.118 AC: 413 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.62
PhyloP100		-0.98
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs17596719;

hg19: chr6-26097194;