rs807209

Variant names:

• chr6-26092637-C-G
• rs807209
• ENST00000470149.5:c.645C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-26092637-C-G
• chr6-26092637-C-T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001406751.1(HFE):​c.645C>G​(p.Gly215Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0082 in 1,614,010 control chromosomes in the GnomAD database, including 721 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.038 (388 hom., cov: 31)
  • Exomes 𝑓: 0.0051 (333 hom.)
• Consequence: HFE NM_001406751.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.226
• Publications: 4 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-26092637-C-G is Benign according to our data. Variant chr6-26092637-C-G is described in ClinVar as Benign. ClinVar VariationId is 1292203.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.226 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406751.1. 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.617-48C>G		intron	N/A	NP_000401.1	Q30201-1
	HFE	NM_001406751.1		c.645C>G	p.Gly215Gly	synonymous	Exon 4 of 7	NP_001393680.1	Q6B0J5
	HFE	NM_001384164.1		c.617-48C>G		intron	N/A	NP_001371093.1	H7C4K4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFE	ENST00000470149.5	TSL:1	c.645C>G	p.Gly215Gly	synonymous	Exon 4 of 7	ENSP00000419725.1	Q6B0J5
	HFE	ENST00000357618.10	TSL:1 MANE Select	c.617-48C>G		intron	N/A	ENSP00000417404.1	Q30201-1
	HFE	ENST00000461397.6	TSL:1	c.617-90C>G		intron	N/A	ENSP00000420802.1	Q30201-3

Frequencies

GnomAD3 genomes AF: 0.0381 AC: 5789 AN: 152106 Hom.: 383 Cov.: 31

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.0326

GnomAD2 exomes AF: 0.0111 AC: 2771 AN: 250314 AF XY: 0.00844

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00223

Gnomad FIN exome AF: 0.0000927

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.00766

GnomAD4 exome AF: 0.00508 AC: 7424 AN: 1461786 Hom.: 333 Cov.: 33 AF XY: 0.00457 AC XY: 3323 AN XY: 727196

African (AFR) AF: 0.133 AC: 4449 AN: 33464

American (AMR) AF: 0.0110 AC: 492 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00272 AC: 71 AN: 26136

East Asian (EAS) AF: 0.00108 AC: 43 AN: 39700

South Asian (SAS) AF: 0.000985 AC: 85 AN: 86258

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53344

Middle Eastern (MID) AF: 0.0196 AC: 113 AN: 5768

European-Non Finnish (NFE) AF: 0.00140 AC: 1560 AN: 1111996

Other (OTH) AF: 0.0100 AC: 605 AN: 60396

GnomAD4 genome AF: 0.0382 AC: 5814 AN: 152224 Hom.: 388 Cov.: 31 AF XY: 0.0369 AC XY: 2749 AN XY: 74418

African (AFR) AF: 0.128 AC: 5304 AN: 41508

American (AMR) AF: 0.0182 AC: 279 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5180

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00198 AC: 135 AN: 68016

Other (OTH) AF: 0.0322 AC: 68 AN: 2110

Alfa AF: 0.00219 Hom.: 1

Bravo AF: 0.0442

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.7
DANN	Benign	0.65
PhyloP100		0.23
PromoterAI		-0.073	Neutral
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: rs807209; hg19: chr6-26092865;