NM_003227.4:c.714C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003227.4(TFR2):c.714C>G(p.Ile238Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00989 in 1,613,732 control chromosomes in the GnomAD database, including 733 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I238I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.038 ( 331 hom., cov: 30)

Exomes 𝑓: 0.0069 ( 402 hom. )

Consequence

TFR2
NM_003227.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -5.23

Publications

24 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:

LOC124901709 (HGNC:):

LOC124901709 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001814574).

BP6

Variant 7-100633241-G-C is Benign according to our data. Variant chr7-100633241-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003227.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFR2	NM_003227.4	MANE Select	c.714C>G	p.Ile238Met	missense	Exon 5 of 18	NP_003218.2
	TFR2	NM_001206855.3		c.201C>G	p.Ile67Met	missense	Exon 2 of 15	NP_001193784.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TFR2	ENST00000223051.8	TSL:1 MANE Select	c.714C>G	p.Ile238Met	missense	Exon 5 of 18	ENSP00000223051.3
TFR2	ENST00000462107.1	TSL:5	c.714C>G	p.Ile238Met	missense	Exon 6 of 19	ENSP00000420525.1
TFR2	ENST00000431692.5	TSL:5	c.714C>G	p.Ile238Met	missense	Exon 5 of 16	ENSP00000413905.1

Frequencies

GnomAD3 genomes

AF:

0.0382

AC:

5811

AN:

152102

Hom.:

329

Cov.:

show subpopulations

Gnomad AFR

AF:

0.122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0108

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0625

Gnomad SAS

AF:

0.0284

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.0258

GnomAD2 exomes

AF:

0.0177

AC:

4398

AN:

248788

AF XY:

0.0161

show subpopulations

Gnomad AFR exome

AF:

0.125

Gnomad AMR exome

AF:

0.00797

Gnomad ASJ exome

AF:

0.000299

Gnomad EAS exome

AF:

0.0646

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000784

Gnomad OTH exome

AF:

0.00987

GnomAD4 exome

AF:

0.00694

AC:

10147

AN:

1461512

Hom.:

402

Cov.:

AF XY:

0.00717

AC XY:

5212

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.125

AC:

4184

AN:

33470

American (AMR)

AF:

0.00834

AC:

373

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26122

East Asian (EAS)

AF:

0.0554

AC:

2198

AN:

39692

South Asian (SAS)

AF:

0.0242

AC:

2083

AN:

86252

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53236

Middle Eastern (MID)

AF:

0.0113

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000463

AC:

515

AN:

1111868

Other (OTH)

AF:

0.0120

AC:

725

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

651

1302

1953

2604

3255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

202

404

606

808

1010

<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:

0.0382

AC:

5811

AN:

152220

Hom.:

331

Cov.:

AF XY:

0.0374

AC XY:

2785

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.122

AC:

5075

AN:

41534

American (AMR)

AF:

0.0108

AC:

165

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0618

AC:

319

AN:

5158

South Asian (SAS)

AF:

0.0284

AC:

137

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000838

AC:

AN:

68002

Other (OTH)

AF:

0.0255

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

261

522

784

1045

1306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.00741

Hom.:

Bravo

AF:

0.0420

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.125

AC:

550

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0202

AC:

2450

Asia WGS

AF:

0.0340

AC:

118

AN:

3478

EpiCase

AF:

0.00131

EpiControl

AF:

0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hemochromatosis type 3

Benign:2Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Apr 08, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not provided

Benign:2

Feb 18, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30998180)

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

Aug 18, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary hemochromatosis

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.47

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.079

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.90

PhyloP100

-5.2

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.010

REVEL

Benign

0.061

Sift

Uncertain

0.010

Sift4G

Uncertain

0.028

Polyphen

0.43

Vest4

0.089

MPC

0.80

ClinPred

0.033

GERP RS

-12

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.0

Varity_R

0.15

gMVP

0.46

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over