dbSNP rs4434553: TFR2:c.-258+123T>C (chr7-100642568-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+123T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 151,980 control chromosomes in the GnomAD database, including 12,680 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 0.39 ( 12632 hom., cov: 29)

Exomes 𝑓: 0.46 ( 48 hom. )

Consequence

TFR2
ENST00000462107.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.682

Publications

21 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=-0.69).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.481 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+123T>C		intron_variant	Intron 1 of 18	5		ENSP00000420525.1		Q9UP52-1
TFR2	ENST00000474947.1 link	n.89+123T>C		intron_variant	Intron 1 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.393

AC:

59485

AN:

151462

Hom.:

12635

Cov.:

show subpopulations

Gnomad AFR

AF:

0.296

Gnomad AMI

AF:

0.365

Gnomad AMR

AF:

0.339

Gnomad ASJ

AF:

0.560

Gnomad EAS

AF:

0.104

Gnomad SAS

AF:

0.346

Gnomad FIN

AF:

0.350

Gnomad MID

AF:

0.538

Gnomad NFE

AF:

0.485

Gnomad OTH

AF:

0.423

GnomAD4 exome

AF:

0.455

AC:

183

AN:

402

Hom.:

AF XY:

0.462

AC XY:

110

AN XY:

238

show subpopulations

African (AFR)

AF:

0.250

AC:

AN:

American (AMR)

AF:

0.500

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.0500

AC:

AN:

South Asian (SAS)

AF:

0.333

AC:

AN:

European-Finnish (FIN)

AF:

0.354

AC:

AN:

Middle Eastern (MID)

AF:

0.750

AC:

AN:

European-Non Finnish (NFE)

AF:

0.504

AC:

141

AN:

280

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

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:

0.392

AC:

59489

AN:

151578

Hom.:

12632

Cov.:

AF XY:

0.386

AC XY:

28613

AN XY:

74032

show subpopulations

African (AFR)

AF:

0.296

AC:

12228

AN:

41286

American (AMR)

AF:

0.338

AC:

5152

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.560

AC:

1941

AN:

3466

East Asian (EAS)

AF:

0.104

AC:

532

AN:

5140

South Asian (SAS)

AF:

0.345

AC:

1645

AN:

4774

European-Finnish (FIN)

AF:

0.350

AC:

3691

AN:

10548

Middle Eastern (MID)

AF:

0.551

AC:

161

AN:

292

European-Non Finnish (NFE)

AF:

0.485

AC:

32925

AN:

67826

Other (OTH)

AF:

0.419

AC:

882

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1734

3468

5203

6937

8671

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

566

1132

1698

2264

2830

<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:

0.457

Hom.:

29715

Bravo

AF:

0.386

Asia WGS

AF:

0.219

AC:

767

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.32

PhyloP100

0.68

PromoterAI

-0.013

Neutral

(source)

Mutation Taster

=100/0

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