rs143662783

Variant names:

• chr6-26087490-C-T
• rs143662783
• NM_000410.4:c.50C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-26087490-C-T
• chr6-26087490-C-G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000410.4(HFE):​c.50C>T​(p.Thr17Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000768 in 1,613,906 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T17T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (2 hom.)
• Consequence: HFE NM_000410.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 B:2
• Conservation: PhyloP100: -0.0900
• 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]

HFE-AS1 (HGNC:55168): (HFE antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039761215).
• BS2: High Homozygotes in GnomAdExome4 at 2 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.50C>T	p.Thr17Ile	missense	Exon 1 of 6	NP_000401.1	Q30201-1
	HFE	NM_001384164.1		c.50C>T	p.Thr17Ile	missense	Exon 1 of 7	NP_001371093.1	H7C4K4
	HFE	NM_001406751.1		c.50C>T	p.Thr17Ile	missense	Exon 1 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.50C>T	p.Thr17Ile	missense	Exon 1 of 6	ENSP00000417404.1	Q30201-1
	HFE	ENST00000470149.5	TSL:1	c.50C>T	p.Thr17Ile	missense	Exon 1 of 7	ENSP00000419725.1	Q6B0J5
	HFE	ENST00000461397.6	TSL:1	c.50C>T	p.Thr17Ile	missense	Exon 1 of 6	ENSP00000420802.1	Q30201-3

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000443 AC: 111 AN: 250420 AF XY: 0.000391

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000893

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000803 AC: 1173 AN: 1461678 Hom.: 2 Cov.: 30 AF XY: 0.000744 AC XY: 541 AN XY: 727142

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00101 AC: 1124 AN: 1111912

Other (OTH) AF: 0.000530 AC: 32 AN: 60384

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74368

African (AFR) AF: 0.000121 AC: 5 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 68038

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000652 Hom.: 1

Bravo AF: 0.000419

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000437 AC: 53

EpiCase AF: 0.000872

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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	0.19
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.090
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.035
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.046	D
Polyphen		0.021	B
Vest4		0.20
MVP		0.74
MPC		0.62
ClinPred		0.12	T
GERP RS		3.2
PromoterAI		0.073	Neutral
Varity_R		0.059
gMVP		0.53
Mutation Taster		=94/6	polymorphism

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: rs143662783; hg19: chr6-26087718;