rs111033558

Positions:

• chr6-26093215-G-C
• chr6-26093215-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000410.4(HFE):​c.989G>C​(p.Arg330Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,554 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HFE NM_000410.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.337

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19082013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HFE	NM_000410.4	c.989G>C	p.Arg330Thr	missense_variant	5/6	ENST00000357618.10	NP_000401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HFE	ENST00000357618.10	c.989G>C	p.Arg330Thr	missense_variant	5/6	1	NM_000410.4	ENSP00000417404	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460554 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726684

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Uncertain	0.44	.;.;.;.;.;T;T;.;.;.;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.10	N
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.5	.;.;.;.;.;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.4	N;N;D;N;N;N;D;N;D;D;N;D
REVEL	Benign	0.14
Sift	Benign	0.11	T;D;D;D;T;T;T;D;T;D;T;D
Sift4G	Benign	0.11	T;D;D;T;T;T;T;T;T;T;T;D
Polyphen		0.76	P;D;.;P;D;P;P;D;P;P;.;.
Vest4		0.52
MVP		0.95
MPC		0.90
ClinPred		0.32	T
GERP RS		-1.2
Varity_R		0.11
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs111033558; hg19: chr6-26093443;