rs149342416

Variant names:

• chr6-26087458-G-C
• rs149342416
• NM_000410.4:c.18G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000410.4(HFE):​c.18G>C​(p.Arg6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: HFE NM_000410.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:12
• Conservation: PhyloP100: 0.671
• Publications: 13 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025996417).

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.18G>C	p.Arg6Ser	missense	Exon 1 of 6	NP_000401.1	Q30201-1
	HFE	NM_001384164.1		c.18G>C	p.Arg6Ser	missense	Exon 1 of 7	NP_001371093.1	H7C4K4
	HFE	NM_001406751.1		c.18G>C	p.Arg6Ser	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.18G>C	p.Arg6Ser	missense	Exon 1 of 6	ENSP00000417404.1	Q30201-1
	HFE	ENST00000470149.5	TSL:1	c.18G>C	p.Arg6Ser	missense	Exon 1 of 7	ENSP00000419725.1	Q6B0J5
	HFE	ENST00000461397.6	TSL:1	c.18G>C	p.Arg6Ser	missense	Exon 1 of 6	ENSP00000420802.1	Q30201-3

Frequencies

GnomAD3 genomes AF: 0.000696 AC: 106 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000690 AC: 173 AN: 250788 AF XY: 0.000604

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00123

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.00106 AC: 1552 AN: 1461786 Hom.: 0 Cov.: 30 AF XY: 0.000996 AC XY: 724 AN XY: 727194

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000671 AC: 30 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53386

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5752

European-Non Finnish (NFE) AF: 0.00129 AC: 1439 AN: 1111972

Other (OTH) AF: 0.00111 AC: 67 AN: 60386

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74366

African (AFR) AF: 0.000555 AC: 23 AN: 41458

American (AMR) AF: 0.000523 AC: 8 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68030

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00114 Hom.: 1

Bravo AF: 0.000703

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000667 AC: 81

EpiCase AF: 0.00109

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	5	-	not provided (5)
-	3	-	Hemochromatosis type 1 (3)
-	1	-	Hereditary hemochromatosis (1)
-	1	-	HFE-related disorder (1)
-	1	-	not specified (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	0.24
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.67
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.22
Sift	Uncertain	0.011	D
Sift4G	Benign	0.20	T
Polyphen		0.19	B
Vest4		0.41
MutPred		0.79		Loss of methylation at R6 (P = 0.0045)
MVP		0.73
MPC		0.29
ClinPred		0.035	T
GERP RS		2.9
PromoterAI		-0.11	Neutral
Varity_R		0.096
gMVP		0.59
Mutation Taster		=0/100	disease causing

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: rs149342416; hg19: chr6-26087686;