NM_000410.4:c.187C>G

Variant names:

• chr6-26090951-C-G
• rs1799945
• NM_000410.4:c.187C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PS3 PP5 BP4

The NM_000410.4(HFE):​c.187C>G​(p.His63Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,613,898 control chromosomes in the GnomAD database, including 15,277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars). ClinVar reports functional evidence for this variant: "SCV000461883: The p.His63Asp variant is predicted to disrupt a pH-dependent intramolecular salt bridge in the alpha-2 domain, thereby affecting interaction of the protein with the transferrin receptor (PMID:20301613)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. H63H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.10 (1005 hom., cov: 31)
  • Exomes 𝑓: 0.14 (14272 hom.)
• Consequence: HFE NM_000410.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:48 U:3 B:1 O:6
• Conservation: PhyloP100: 1.87
• Publications: 2012 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: Uncertain_significance. The variant received 4 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000461883: The p.His63Asp variant is predicted to disrupt a pH-dependent intramolecular salt bridge in the alpha-2 domain, thereby affecting interaction of the protein with the transferrin receptor (PMID: 20301613).; SCV001519563: "While p.His63Asp was shown to have normal levels of association with beta2-globulin and expression of HFE on the cell surface in contrast to impairment observed in cells with the other common pathogenic variant p.Cys282Tyr (e.g. Waheed_1997), p.His63Asp was shown to induce ER-stress in-vitro and in a transgenic mouse model (e.g. Liu_2011). Transgenic mice expressing the murine equivalent of this variant were also reported to have increased iron storage and decreased levels of iron mobilization at 12 months of age (e.g. Nandar_2013). The variant has also been reported to alter the expression levels of several genes involved in sphingolipid metabolism (e.g. Ali-Rahmani_2011) and to affect cellular glutamate levels (e.g. Mitchell_2011)."; SCV005061024: Experimental studies have shown that this missense change affects HFE function (Tomatsu et al., 2003).; SCV005417670: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV006582525: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12429850, 14673107, 9162021, 9356458).; SCV000577565: Published functional studies demonstrate a damaging effect (Nandar et al., 2013; Mitchell et al., 2011); SCV001552099: Functional studies show that the HFE p.H63D variant impacts brain iron homeostasis (Nandar_2013_PMID: 23429074).; SCV000219176: Experimental studies have shown that this missense change affects HFE function (PMID: 9162021, 9356458, 12429850, 14673107).
• PP5: Variant 6-26090951-C-G is Pathogenic according to our data. Variant chr6-26090951-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity|other. ClinVar VariationId is 10.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015847087). . Strength limited to SUPPORTING due to the PP5.

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.187C>G	p.His63Asp	missense	Exon 2 of 6	NP_000401.1	Q30201-1
	HFE	NM_001384164.1		c.187C>G	p.His63Asp	missense	Exon 2 of 7	NP_001371093.1	H7C4K4
	HFE	NM_001406751.1		c.187C>G	p.His63Asp	missense	Exon 2 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.187C>G	p.His63Asp	missense	Exon 2 of 6	ENSP00000417404.1	Q30201-1
	HFE	ENST00000470149.5	TSL:1	c.187C>G	p.His63Asp	missense	Exon 2 of 7	ENSP00000419725.1	Q6B0J5
	HFE	ENST00000461397.6	TSL:1	c.187C>G	p.His63Asp	missense	Exon 2 of 6	ENSP00000420802.1	Q30201-3

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15453 AN: 152026 Hom.: 1005 Cov.: 31

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.0272

Gnomad SAS AF: 0.0777

Gnomad FIN AF: 0.0959

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.109 AC: 27472 AN: 251484 AF XY: 0.112

Gnomad AFR exome AF: 0.0274

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.0347

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.135 AC: 197513 AN: 1461754 Hom.: 14272 Cov.: 34 AF XY: 0.134 AC XY: 97535 AN XY: 727184

African (AFR) AF: 0.0276 AC: 923 AN: 33480

American (AMR) AF: 0.103 AC: 4612 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 3039 AN: 26132

East Asian (EAS) AF: 0.0312 AC: 1240 AN: 39700

South Asian (SAS) AF: 0.0795 AC: 6859 AN: 86256

European-Finnish (FIN) AF: 0.106 AC: 5650 AN: 53420

Middle Eastern (MID) AF: 0.122 AC: 705 AN: 5768

European-Non Finnish (NFE) AF: 0.150 AC: 166948 AN: 1111888

Other (OTH) AF: 0.125 AC: 7537 AN: 60386

GnomAD4 genome AF: 0.102 AC: 15444 AN: 152144 Hom.: 1005 Cov.: 31 AF XY: 0.0991 AC XY: 7371 AN XY: 74366

African (AFR) AF: 0.0296 AC: 1227 AN: 41514

American (AMR) AF: 0.110 AC: 1681 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 419 AN: 3468

East Asian (EAS) AF: 0.0269 AC: 139 AN: 5172

South Asian (SAS) AF: 0.0773 AC: 373 AN: 4824

European-Finnish (FIN) AF: 0.0959 AC: 1015 AN: 10580

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10219 AN: 67976

Other (OTH) AF: 0.130 AC: 274 AN: 2112

Alfa AF: 0.136 Hom.: 1184

Bravo AF: 0.100

TwinsUK AF: 0.143 AC: 530

ALSPAC AF: 0.136 AC: 526

ESP6500AA AF: 0.0315 AC: 139

ESP6500EA AF: 0.151 AC: 1301

ExAC AF: 0.107 AC: 12942

Asia WGS AF: 0.0630 AC: 218 AN: 3478

EpiCase AF: 0.148

EpiControl AF: 0.146

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; other

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
30	1	-	Hemochromatosis type 1 (33)
13	-	-	not provided (14)
-	1	1	not specified (2)
1	-	-	Alzheimer disease;C0162532:Variegate porphyria;C0268323:Familial porphyria cutanea tarda;C2673520:Microvascular complications of diabetes, susceptibility to, 7;C3280096:TRANSFERRIN SERUM LEVEL QUANTITATIVE TRAIT LOCUS 2;C3469186:Hemochromatosis type 1 (1)
1	-	-	Cardiomyopathy (1)
1	-	-	Hereditary hemochromatosis (2)
-	1	-	Neuroendocrine neoplasm (1)
1	-	-	See cases (1)
1	-	-	Variegate porphyria (1)
-	-	-	Bronze diabetes (1)
-	-	-	Cystic fibrosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0016	T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.8	L
PhyloP100		1.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.016	D
Sift4G	Benign	0.15	T
Polyphen		0.15	B
Vest4		0.30
MPC		0.99
ClinPred		0.012	T
GERP RS		3.5
Varity_R		0.45
gMVP		0.99
Mutation Taster		=59/41	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1799945; hg19: chr6-26091179; COSMIC: COSV58513169; COSMIC: COSV58513169;