NM_000410.4:c.*2930T>C

Variant names:

• chr6-26097156-T-C
• rs6918586
• NM_000410.4:c.*2930T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000410.4(HFE):​c.*2930T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 152,280 control chromosomes in the GnomAD database, including 16,052 homozygotes. 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: 𝑓 0.44 (16029 hom., cov: 32)
  • Exomes 𝑓: 0.44 (23 hom.)
• Consequence: HFE NM_000410.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.74
• Publications: 27 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFE	NM_000410.4	MANE Select	c.*2930T>C		3_prime_UTR	Exon 6 of 6	NP_000401.1
	HFE	NM_001384164.1		c.*2745T>C		3_prime_UTR	Exon 7 of 7	NP_001371093.1
	HFE	NM_001406751.1		c.*2930T>C		3_prime_UTR	Exon 7 of 7	NP_001393680.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFE	ENST00000357618.10	TSL:1 MANE Select	c.*2930T>C		3_prime_UTR	Exon 6 of 6	ENSP00000417404.1
	HFE	ENST00000714172.1		c.*2745T>C		3_prime_UTR	Exon 5 of 5	ENSP00000519461.1
	HFE	ENST00000714164.1		c.*2930T>C		3_prime_UTR	Exon 2 of 2	ENSP00000519453.1

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66884 AN: 151946 Hom.: 16009 Cov.: 32

Gnomad AFR AF: 0.609

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.490

GnomAD4 exome AF: 0.435 AC: 94 AN: 216 Hom.: 23 Cov.: 0 AF XY: 0.433 AC XY: 52 AN XY: 120

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AF: 0.333 AC: 2 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AF: 0.417 AC: 5 AN: 12

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.446 AC: 83 AN: 186

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.440 AC: 66937 AN: 152064 Hom.: 16029 Cov.: 32 AF XY: 0.431 AC XY: 32024 AN XY: 74358

African (AFR) AF: 0.609 AC: 25257 AN: 41450

American (AMR) AF: 0.400 AC: 6110 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 1815 AN: 3466

East Asian (EAS) AF: 0.152 AC: 786 AN: 5176

South Asian (SAS) AF: 0.377 AC: 1821 AN: 4828

European-Finnish (FIN) AF: 0.248 AC: 2622 AN: 10582

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.399 AC: 27118 AN: 67966

Other (OTH) AF: 0.484 AC: 1021 AN: 2110

Alfa AF: 0.413 Hom.: 21823

Bravo AF: 0.460

Asia WGS AF: 0.287 AC: 1000 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.0
DANN	Benign	0.67
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs6918586; hg19: chr6-26097384;