6-26091362-A-T

Variant names:

• chr6-26091362-A-T
• NM_000410.4:c.389A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000410.4(HFE):​c.389A>T​(p.Asn130Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.982

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 4 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity HFE_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HFE	NM_000410.4	c.389A>T	p.Asn130Ile	missense_variant	Exon 3 of 6	ENST00000357618.10	NP_000401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HFE	ENST00000357618.10	c.389A>T	p.Asn130Ile	missense_variant	Exon 3 of 6	1	NM_000410.4	ENSP00000417404.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	.;.;T;T;.;.;T
Eigen	Benign	0.060
Eigen_PC	Benign	-0.080
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.1	.;.;M;.;M;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D;D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		0.97	D;P;D;D;D;D;.
Vest4		0.51
MutPred		0.65		.;.;Loss of disorder (P = 0.0178);Loss of disorder (P = 0.0178);Loss of disorder (P = 0.0178);.;Loss of disorder (P = 0.0178);
MVP		0.90
MPC		0.95
ClinPred		0.97	D
GERP RS		1.6
Varity_R		0.84
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-26091590;