Genetic Variant TFR2:c.-258+18T>C (chr7-100642673-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000462107.1(TFR2):c.-258+18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 154,586 control chromosomes in the GnomAD database, including 32,651 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.65 ( 31961 hom., cov: 27)

Exomes 𝑓: 0.62 ( 690 hom. )

Consequence

TFR2
ENST00000462107.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.07

Publications

43 publications found

Variant links:

Genes affected

TFR2 (HGNC:11762): (transferrin receptor 2) This gene encodes a single-pass type II membrane protein, which is a member of the transferrin receptor-like family. This protein mediates cellular uptake of transferrin-bound iron, and may be involved in iron metabolism, hepatocyte function and erythrocyte differentiation. Mutations in this gene have been associated with hereditary hemochromatosis type III. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, May 2011]

TFR2 Gene-Disease associations (from GenCC):

hemochromatosis type 3
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

TFR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000462107.1 link	c.-258+18T>C		intron_variant	Intron 1 of 18	5		ENSP00000420525.1		Q9UP52-1
TFR2	ENST00000474947.1 link	n.89+18T>C		intron_variant	Intron 1 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.647

AC:

97795

AN:

151064

Hom.:

31945

Cov.:

show subpopulations

Gnomad AFR

AF:

0.670

Gnomad AMI

AF:

0.508

Gnomad AMR

AF:

0.728

Gnomad ASJ

AF:

0.691

Gnomad EAS

AF:

0.784

Gnomad SAS

AF:

0.635

Gnomad FIN

AF:

0.535

Gnomad MID

AF:

0.736

Gnomad NFE

AF:

0.622

Gnomad OTH

AF:

0.669

GnomAD4 exome

AF:

0.623

AC:

2121

AN:

3404

Hom.:

690

Cov.:

AF XY:

0.619

AC XY:

1169

AN XY:

1888

show subpopulations

African (AFR)

AF:

0.674

AC:

AN:

American (AMR)

AF:

0.685

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.607

AC:

AN:

East Asian (EAS)

AF:

0.846

AC:

193

AN:

228

South Asian (SAS)

AF:

0.656

AC:

AN:

European-Finnish (FIN)

AF:

0.512

AC:

210

AN:

410

Middle Eastern (MID)

AF:

0.786

AC:

AN:

European-Non Finnish (NFE)

AF:

0.606

AC:

1373

AN:

2266

Other (OTH)

AF:

0.724

AC:

152

AN:

210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

108

144

180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.647

AC:

97851

AN:

151182

Hom.:

31961

Cov.:

AF XY:

0.649

AC XY:

47922

AN XY:

73806

show subpopulations

African (AFR)

AF:

0.670

AC:

27556

AN:

41158

American (AMR)

AF:

0.729

AC:

11091

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.691

AC:

2392

AN:

3460

East Asian (EAS)

AF:

0.784

AC:

3967

AN:

5062

South Asian (SAS)

AF:

0.633

AC:

3008

AN:

4750

European-Finnish (FIN)

AF:

0.535

AC:

5625

AN:

10506

Middle Eastern (MID)

AF:

0.747

AC:

218

AN:

292

European-Non Finnish (NFE)

AF:

0.622

AC:

42123

AN:

67730

Other (OTH)

AF:

0.671

AC:

1412

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1701

3401

5102

6802

8503

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

786

1572

2358

3144

3930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.639

Hom.:

127094

Bravo

AF:

0.663

Asia WGS

AF:

0.687

AC:

2392

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

1.1

PromoterAI

-0.062

Neutral

(source)

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over