NM_000410.4:c.884T>C

Variant names:

• chr6-26092952-T-C
• rs143175221
• NM_000410.4:c.884T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000410.4(HFE):​c.884T>C​(p.Val295Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000417 in 1,614,014 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00060 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00040 (1 hom.)
• Consequence: HFE NM_000410.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: -0.637
• Publications: 15 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050828755).
• BP6: Variant 6-26092952-T-C is Benign according to our data. Variant chr6-26092952-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 461195.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000604 (92/152304) while in subpopulation EAS AF = 0.00425 (22/5180). AF 95% confidence interval is 0.00287. There are 1 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.884T>C	p.Val295Ala	missense	Exon 4 of 6	NP_000401.1	Q30201-1
	HFE	NM_001384164.1		c.884T>C	p.Val295Ala	missense	Exon 4 of 7	NP_001371093.1	H7C4K4
	HFE	NM_001406751.1		c.875T>C	p.Val292Ala	missense	Exon 5 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.884T>C	p.Val295Ala	missense	Exon 4 of 6	ENSP00000417404.1	Q30201-1
	HFE	ENST00000470149.5	TSL:1	c.875T>C	p.Val292Ala	missense	Exon 5 of 7	ENSP00000419725.1	Q6B0J5
	HFE	ENST00000461397.6	TSL:1	c.842T>C	p.Val281Ala	missense	Exon 4 of 6	ENSP00000420802.1	Q30201-3

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152186 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000841 AC: 211 AN: 251032 AF XY: 0.000899

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00500

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000344

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000397 AC: 581 AN: 1461710 Hom.: 1 Cov.: 34 AF XY: 0.000459 AC XY: 334 AN XY: 727164

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.000917 AC: 41 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00189 AC: 75 AN: 39700

South Asian (SAS) AF: 0.00152 AC: 131 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000706 AC: 4 AN: 5662

European-Non Finnish (NFE) AF: 0.000272 AC: 303 AN: 1111960

Other (OTH) AF: 0.000414 AC: 25 AN: 60384

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152304 Hom.: 1 Cov.: 31 AF XY: 0.000752 AC XY: 56 AN XY: 74470

African (AFR) AF: 0.0000722 AC: 3 AN: 41572

American (AMR) AF: 0.00275 AC: 42 AN: 15288

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

East Asian (EAS) AF: 0.00425 AC: 22 AN: 5180

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68026

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000395 Hom.: 0

Bravo AF: 0.000710

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000749 AC: 91

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	2	-	Hemochromatosis type 1 (2)
-	-	1	Hereditary hemochromatosis (1)
-	-	1	HFE-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	0.73
DANN	Benign	0.46
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0077	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.030	N
PhyloP100		-0.64
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.23
Sift	Benign	0.55	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.23
MVP		0.87
MPC		0.28
ClinPred		0.0022	T
GERP RS		0.44
PromoterAI		0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.21
Mutation Taster		=8/92	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: rs143175221; hg19: chr6-26093180;