rs707889

Variant names:

• chr6-26095703-G-A
• rs707889
• NM_000410.4:c.*1477G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-26095703-G-A
• chr6-26095703-G-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.*1477G>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 0.214 in 151,964 control chromosomes in the GnomAD database, including 3,729 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 0.21 (3728 hom., cov: 31)
  • Exomes 𝑓: 0.38 (1 hom.)
• Consequence: HFE NM_000410.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.108
• Publications: 24 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=-0.65).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.241 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.*1477G>A		3_prime_UTR	Exon 6 of 6	NP_000401.1
	HFE	NM_001384164.1		c.*1292G>A		3_prime_UTR	Exon 7 of 7	NP_001371093.1
	HFE	NM_001406751.1		c.*1477G>A		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.*1477G>A		3_prime_UTR	Exon 6 of 6	ENSP00000417404.1
	HFE	ENST00000714170.1		c.*1477G>A		3_prime_UTR	Exon 7 of 7	ENSP00000519459.1
	HFE	ENST00000714172.1		c.*1292G>A		3_prime_UTR	Exon 5 of 5	ENSP00000519461.1

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32485 AN: 151828 Hom.: 3722 Cov.: 31

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.0802

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.188

GnomAD4 exome AF: 0.375 AC: 6 AN: 16 Hom.: 1 Cov.: 0 AF XY: 0.667 AC XY: 4 AN XY: 6

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AF: 1.00 AC: 2 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.200 AC: 2 AN: 10

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.214 AC: 32513 AN: 151948 Hom.: 3728 Cov.: 31 AF XY: 0.208 AC XY: 15437 AN XY: 74292

African (AFR) AF: 0.245 AC: 10145 AN: 41396

American (AMR) AF: 0.155 AC: 2369 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 445 AN: 3466

East Asian (EAS) AF: 0.151 AC: 778 AN: 5162

South Asian (SAS) AF: 0.0792 AC: 382 AN: 4822

European-Finnish (FIN) AF: 0.220 AC: 2326 AN: 10558

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15318 AN: 67948

Other (OTH) AF: 0.188 AC: 397 AN: 2112

Alfa AF: 0.203 Hom.: 6342

Bravo AF: 0.212

Asia WGS AF: 0.145 AC: 505 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.1
DANN	Benign	0.61
PhyloP100		0.11
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: rs707889; hg19: chr6-26095931;