rs35201683

Variant names:

• chr6-26094205-C-T
• rs35201683
• NM_000410.4:c.1026C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-26094205-C-T
• chr6-26094205-C-A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000410.4(HFE):​c.1026C>T​(p.Tyr342Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000976 in 1,613,918 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0047 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (5 hom.)
• Consequence: HFE NM_000410.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.840
• Publications: 8 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=-0.63).
• BP6: Variant 6-26094205-C-T is Benign according to our data. Variant chr6-26094205-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 237780.
• BP7: Synonymous conserved (PhyloP=-0.84 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00473 (721/152276) while in subpopulation AFR AF = 0.0153 (636/41544). AF 95% confidence interval is 0.0143. There are 7 homozygotes in GnomAd4. There are 314 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.1026C>T	p.Tyr342Tyr	synonymous	Exon 6 of 6	NP_000401.1	Q30201-1
	HFE	NM_001384164.1		c.1026C>T	p.Tyr342Tyr	synonymous	Exon 6 of 7	NP_001371093.1	H7C4K4
	HFE	NM_001406751.1		c.1017C>T	p.Tyr339Tyr	synonymous	Exon 7 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.1026C>T	p.Tyr342Tyr	synonymous	Exon 6 of 6	ENSP00000417404.1	Q30201-1
	HFE	ENST00000470149.5	TSL:1	c.1017C>T	p.Tyr339Tyr	synonymous	Exon 7 of 7	ENSP00000419725.1	Q6B0J5
	HFE	ENST00000461397.6	TSL:1	c.984C>T	p.Tyr328Tyr	synonymous	Exon 6 of 6	ENSP00000420802.1	Q30201-3

Frequencies

GnomAD3 genomes AF: 0.00474 AC: 721 AN: 152158 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00136 AC: 341 AN: 251292 AF XY: 0.000810

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000584 AC: 854 AN: 1461642 Hom.: 5 Cov.: 31 AF XY: 0.000538 AC XY: 391 AN XY: 727150

African (AFR) AF: 0.0150 AC: 503 AN: 33478

American (AMR) AF: 0.00179 AC: 80 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53372

Middle Eastern (MID) AF: 0.00263 AC: 15 AN: 5698

European-Non Finnish (NFE) AF: 0.000133 AC: 148 AN: 1111892

Other (OTH) AF: 0.00139 AC: 84 AN: 60390

GnomAD4 genome AF: 0.00473 AC: 721 AN: 152276 Hom.: 7 Cov.: 32 AF XY: 0.00422 AC XY: 314 AN XY: 74454

African (AFR) AF: 0.0153 AC: 636 AN: 41544

American (AMR) AF: 0.00366 AC: 56 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

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

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68020

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00403 Hom.: 1

Bravo AF: 0.00556

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Hemochromatosis type 1 (1)
-	-	1	Hereditary hemochromatosis (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.7
DANN	Benign	0.32
PhyloP100		-0.84
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs35201683; hg19: chr6-26094433;