chr7-100627570-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003227.4(TFR2):c.1767+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00729 in 1,614,130 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0059 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0074 ( 66 hom. )

Consequence

TFR2
NM_003227.4 splice_region, intron

Scores

Splicing: ADA: 0.01185

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.228

Publications

2 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:

ENSG00000298392 (HGNC:):

ENSG00000298392 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 (BayesDel_noAF=-0.77).

BP6

Variant 7-100627570-G-A is Benign according to our data. Variant chr7-100627570-G-A is described in ClinVar as Benign. ClinVar VariationId is 415943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00593 (903/152312) while in subpopulation SAS AF = 0.0106 (51/4830). AF 95% confidence interval is 0.00825. There are 6 homozygotes in GnomAd4. There are 412 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TFR2	NM_003227.4 link	c.1767+7C>T	splice_region_variant, intron_variant	Intron 15 of 17	ENST00000223051.8	NP_003218.2	Q9UP52-1
TFR2	NM_001206855.3 link	c.1254+7C>T	splice_region_variant, intron_variant	Intron 12 of 14		NP_001193784.1	Q9UP52-2
LOC124901709	XR_007060454.1 link	n.434-3586G>A	intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8 link	c.1767+7C>T		splice_region_variant, intron_variant	Intron 15 of 17	1	NM_003227.4	ENSP00000223051.3		Q9UP52-1

Frequencies

GnomAD3 genomes

AF:

0.00594

AC:

904

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.0325

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.00649

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00773

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00703

AC:

1766

AN:

251060

AF XY:

0.00735

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.0303

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00616

Gnomad NFE exome

AF:

0.00693

Gnomad OTH exome

AF:

0.00849

GnomAD4 exome

AF:

0.00743

AC:

10861

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00767

AC XY:

5575

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

33478

American (AMR)

AF:

0.00291

AC:

130

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0304

AC:

795

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0130

AC:

1124

AN:

86256

European-Finnish (FIN)

AF:

0.00622

AC:

332

AN:

53412

Middle Eastern (MID)

AF:

0.0166

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00702

AC:

7808

AN:

1111964

Other (OTH)

AF:

0.00874

AC:

528

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

668

1336

2005

2673

3341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

302

604

906

1208

1510

<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:

0.00593

AC:

903

AN:

152312

Hom.:

Cov.:

AF XY:

0.00553

AC XY:

412

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41570

American (AMR)

AF:

0.00405

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0325

AC:

113

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.0106

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00649

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00773

AC:

526

AN:

68016

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

149

198

248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00734

Hom.:

Bravo

AF:

0.00497

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00725

EpiControl

AF:

0.00700

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TFR2: BP4, BS1, BS2 -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hemochromatosis type 3

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary hemochromatosis

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TFR2-related disorder

Benign:1

Jul 03, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.58

PhyloP100

0.23

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.012

dbscSNV1_RF

Benign

0.15

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over