rs148161858

Variant names:

• chr6-26087508-G-A
• rs148161858
• NM_000410.4:c.68G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-26087508-G-A
• chr6-26087508-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000410.4(HFE):​c.68G>A​(p.Arg23His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000631 in 1,612,782 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R23L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00043 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (3 hom.)
• Consequence: HFE NM_000410.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 0.520
• Publications: 7 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]

HFE-AS1 (HGNC:55168): (HFE antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0096851885).
• BP6: Variant 6-26087508-G-A is Benign according to our data. Variant chr6-26087508-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 356194.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000427 (65/152324) while in subpopulation SAS AF = 0.0029 (14/4832). AF 95% confidence interval is 0.00175. There are 2 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.68G>A	p.Arg23His	missense	Exon 1 of 6	NP_000401.1	Q30201-1
	HFE	NM_001384164.1		c.68G>A	p.Arg23His	missense	Exon 1 of 7	NP_001371093.1	H7C4K4
	HFE	NM_001406751.1		c.68G>A	p.Arg23His	missense	Exon 1 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.68G>A	p.Arg23His	missense	Exon 1 of 6	ENSP00000417404.1	Q30201-1
	HFE	ENST00000470149.5	TSL:1	c.68G>A	p.Arg23His	missense	Exon 1 of 7	ENSP00000419725.1	Q6B0J5
	HFE	ENST00000461397.6	TSL:1	c.68G>A	p.Arg23His	missense	Exon 1 of 6	ENSP00000420802.1	Q30201-3

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152206 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000569 AC: 142 AN: 249394 AF XY: 0.000673

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000999

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.000586

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000652 AC: 952 AN: 1460458 Hom.: 3 Cov.: 30 AF XY: 0.000730 AC XY: 530 AN XY: 726454

African (AFR) AF: 0.0000299 AC: 1 AN: 33456

American (AMR) AF: 0.000224 AC: 10 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00205 AC: 177 AN: 86212

European-Finnish (FIN) AF: 0.000113 AC: 6 AN: 53298

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5752

European-Non Finnish (NFE) AF: 0.000601 AC: 668 AN: 1110976

Other (OTH) AF: 0.00129 AC: 78 AN: 60346

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152324 Hom.: 2 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74484

African (AFR) AF: 0.000192 AC: 8 AN: 41576

American (AMR) AF: 0.000261 AC: 4 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000588 Hom.: 0

Bravo AF: 0.000283

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000585 AC: 71

EpiCase AF: 0.000764

EpiControl AF: 0.000830

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Hemochromatosis type 1 (2)
-	1	1	not provided (2)
-	-	1	Hereditary hemochromatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.29	N
PhyloP100		0.52
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.051
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.36
MVP		0.77
MPC		0.95
ClinPred		0.079	T
GERP RS		2.9
PromoterAI		-0.0078	Neutral
Varity_R		0.053
gMVP		0.55
Mutation Taster		=96/4	polymorphism

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: rs148161858; hg19: chr6-26087736;