rs2032451

Variant names:

• chr6-26091942-G-T
• rs2032451
• NM_000410.4:c.616+353G>T

Variant summary

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

The NM_000410.4(HFE):​c.616+353G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 152,070 control chromosomes in the GnomAD database, including 1,027 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 0.10 (1027 hom., cov: 30)
• Consequence: HFE NM_000410.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.450
• Publications: 16 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 (NFE) allele frequency at 95% confidence interval = 0.149 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.616+353G>T		intron	N/A	NP_000401.1	Q30201-1
	HFE	NM_001384164.1		c.616+353G>T		intron	N/A	NP_001371093.1	H7C4K4
	HFE	NM_001406751.1		c.616+353G>T		intron	N/A	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.616+353G>T		intron	N/A	ENSP00000417404.1	Q30201-1
	HFE	ENST00000470149.5	TSL:1	c.616+353G>T		intron	N/A	ENSP00000419725.1	Q6B0J5
	HFE	ENST00000461397.6	TSL:1	c.616+353G>T		intron	N/A	ENSP00000420802.1	Q30201-3

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15595 AN: 151952 Hom.: 1027 Cov.: 30

Gnomad AFR AF: 0.0303

Gnomad AMI AF: 0.0870

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.0279

Gnomad SAS AF: 0.0779

Gnomad FIN AF: 0.0961

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.137

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.102 AC: 15587 AN: 152070 Hom.: 1027 Cov.: 30 AF XY: 0.100 AC XY: 7442 AN XY: 74336

African (AFR) AF: 0.0302 AC: 1254 AN: 41492

American (AMR) AF: 0.111 AC: 1691 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 420 AN: 3468

East Asian (EAS) AF: 0.0276 AC: 143 AN: 5178

South Asian (SAS) AF: 0.0777 AC: 374 AN: 4812

European-Finnish (FIN) AF: 0.0961 AC: 1016 AN: 10570

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10290 AN: 67952

Other (OTH) AF: 0.136 AC: 287 AN: 2114

Alfa AF: 0.122 Hom.: 193

Bravo AF: 0.101

Asia WGS AF: 0.0630 AC: 218 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.81
DANN	Benign	0.55
PhyloP100		-0.45
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: rs2032451; hg19: chr6-26092170;