6-26093075-T-C

Variant names:

• chr6-26093075-T-C
• rs1800708
• NM_000410.4:c.893-44T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000410.4(HFE):​c.893-44T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0975 in 1,613,128 control chromosomes in the GnomAD database, including 16,337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1789 hom., cov: 31)
  • Exomes 𝑓: 0.096 (14548 hom.)
• Consequence: HFE NM_000410.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.217
• Publications: 17 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-26093075-T-C is Benign according to our data. Variant chr6-26093075-T-C is described in ClinVar as Benign. ClinVar VariationId is 1236293.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HFE	NM_000410.4	c.893-44T>C		intron_variant	Intron 4 of 5	ENST00000357618.10	NP_000401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HFE	ENST00000357618.10	c.893-44T>C		intron_variant	Intron 4 of 5	1	NM_000410.4	ENSP00000417404.1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17448 AN: 152020 Hom.: 1783 Cov.: 31

Gnomad AFR AF: 0.0956

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.0718

Gnomad EAS AF: 0.560

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0630

Gnomad OTH AF: 0.129

GnomAD2 exomes AF: 0.155 AC: 38973 AN: 251106 AF XY: 0.151

Gnomad AFR exome AF: 0.0937

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.0806

Gnomad EAS exome AF: 0.566

Gnomad FIN exome AF: 0.202

Gnomad NFE exome AF: 0.0638

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.0956 AC: 139733 AN: 1460990 Hom.: 14548 Cov.: 33 AF XY: 0.0980 AC XY: 71201 AN XY: 726868

African (AFR) AF: 0.0917 AC: 3068 AN: 33452

American (AMR) AF: 0.231 AC: 10344 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0787 AC: 2055 AN: 26124

East Asian (EAS) AF: 0.622 AC: 24678 AN: 39692

South Asian (SAS) AF: 0.186 AC: 16001 AN: 86226

European-Finnish (FIN) AF: 0.198 AC: 10550 AN: 53406

Middle Eastern (MID) AF: 0.0984 AC: 567 AN: 5762

European-Non Finnish (NFE) AF: 0.0594 AC: 66031 AN: 1111252

Other (OTH) AF: 0.107 AC: 6439 AN: 60374

GnomAD4 genome AF: 0.115 AC: 17471 AN: 152138 Hom.: 1789 Cov.: 31 AF XY: 0.127 AC XY: 9432 AN XY: 74356

African (AFR) AF: 0.0956 AC: 3966 AN: 41496

American (AMR) AF: 0.174 AC: 2657 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0718 AC: 249 AN: 3470

East Asian (EAS) AF: 0.560 AC: 2887 AN: 5158

South Asian (SAS) AF: 0.197 AC: 950 AN: 4822

European-Finnish (FIN) AF: 0.201 AC: 2132 AN: 10584

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0630 AC: 4283 AN: 68012

Other (OTH) AF: 0.132 AC: 278 AN: 2110

Alfa AF: 0.0837 Hom.: 1327

Bravo AF: 0.114

Asia WGS AF: 0.309 AC: 1072 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.7
DANN	Benign	0.62
PhyloP100		0.22
PromoterAI		0.026	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800708; hg19: chr6-26093303; COSMIC: COSV58512748; COSMIC: COSV58512748;