rs1800730

Variant names:

• chr6-26090957-A-T
• rs1800730
• NM_000410.4:c.193A>T
• HFE p.Ser65Cys

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000410.4(HFE):​c.193A>T​(p.Ser65Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0136 in 1,614,088 control chromosomes in the GnomAD database, including 195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 31)
  • Exomes 𝑓: 0.014 (183 hom.)
• Consequence: HFE NM_000410.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:8 B:5 O:1
• Conservation: PhyloP100: 5.10
• Publications: 342 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 -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000410.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.01902759).
• BP6: Variant 6-26090957-A-T is Benign according to our data. Variant chr6-26090957-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00995 (1515/152208) while in subpopulation NFE AF = 0.0154 (1044/68008). AF 95% confidence interval is 0.0146. There are 12 homozygotes in GnomAd4. There are 756 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.193A>T	p.Ser65Cys	missense	Exon 2 of 6	NP_000401.1	Q30201-1
	HFE	NM_001384164.1		c.193A>T	p.Ser65Cys	missense	Exon 2 of 7	NP_001371093.1	H7C4K4
	HFE	NM_001406751.1		c.193A>T	p.Ser65Cys	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.193A>T	p.Ser65Cys	missense	Exon 2 of 6	ENSP00000417404.1	Q30201-1
	HFE	ENST00000470149.5	TSL:1	c.193A>T	p.Ser65Cys	missense	Exon 2 of 7	ENSP00000419725.1	Q6B0J5
	HFE	ENST00000461397.6	TSL:1	c.193A>T	p.Ser65Cys	missense	Exon 2 of 6	ENSP00000420802.1	Q30201-3

Frequencies

GnomAD3 genomes AF: 0.00997 AC: 1516 AN: 152090 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0154

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.0102 AC: 2575 AN: 251490 AF XY: 0.0101

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00489

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0217

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0140 AC: 20501 AN: 1461880 Hom.: 183 Cov.: 34 AF XY: 0.0137 AC XY: 9989 AN XY: 727244

African (AFR) AF: 0.00209 AC: 70 AN: 33480

American (AMR) AF: 0.00474 AC: 212 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00306 AC: 80 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.000997 AC: 86 AN: 86258

European-Finnish (FIN) AF: 0.0228 AC: 1216 AN: 53420

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0163 AC: 18157 AN: 1112000

Other (OTH) AF: 0.0111 AC: 668 AN: 60394

GnomAD4 genome AF: 0.00995 AC: 1515 AN: 152208 Hom.: 12 Cov.: 31 AF XY: 0.0102 AC XY: 756 AN XY: 74416

African (AFR) AF: 0.00289 AC: 120 AN: 41532

American (AMR) AF: 0.00667 AC: 102 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.0188 AC: 199 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0154 AC: 1044 AN: 68008

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.0136 Hom.: 11

Bravo AF: 0.00887

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	1	Hemochromatosis type 1 (5)
-	2	2	not provided (4)
-	2	1	not specified (3)
-	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	Hereditary hemochromatosis (1)
-	1	-	HFE-related disorder (1)
-	1	-	Variegate porphyria;C0268323:Familial porphyria cutanea tarda;C1863052:Alzheimer disease type 1;C2673520:Microvascular complications of diabetes, susceptibility to, 7;C3280096:TRANSFERRIN SERUM LEVEL QUANTITATIVE TRAIT LOCUS 2;C3469186:Hemochromatosis type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.019	T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		5.1
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Varity_R		0.79
gMVP		0.92
Mutation Taster		=50/50

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: rs1800730;

hg19: chr6-26091185;