rs35704760

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_003227.4(TFR2):c.1770C>T(p.Asp590Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,611,606 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 11 hom., cov: 33)

Exomes 𝑓: 0.0038 ( 73 hom. )

Consequence

TFR2
NM_003227.4 splice_region, synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -4.30

Publications

4 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 -16 ACMG points.

BP6

Variant 7-100627489-G-A is Benign according to our data. Variant chr7-100627489-G-A is described in ClinVar as Benign. ClinVar VariationId is 21368.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 = 0.00349 (531/152326) while in subpopulation SAS AF = 0.0141 (68/4830). AF 95% confidence interval is 0.0114. There are 11 homozygotes in GnomAd4. There are 272 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFR2	NM_003227.4 link	c.1770C>T	p.Asp590Asp	splice_region_variant, synonymous_variant	Exon 16 of 18	ENST00000223051.8	NP_003218.2	Q9UP52-1
TFR2	NM_001206855.3 link	c.1257C>T	p.Asp419Asp	splice_region_variant, synonymous_variant	Exon 13 of 15		NP_001193784.1	Q9UP52-2
LOC124901709	XR_007060454.1 link	n.434-3667G>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.1770C>T	p.Asp590Asp	splice_region_variant, synonymous_variant	Exon 16 of 18	1	NM_003227.4	ENSP00000223051.3		Q9UP52-1

Frequencies

GnomAD3 genomes

AF:

0.00348

AC:

529

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.0527

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0139

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00243

Gnomad OTH

AF:

0.00671

GnomAD2 exomes

AF:

0.00641

AC:

1571

AN:

245126

AF XY:

0.00693

show subpopulations

Gnomad AFR exome

AF:

0.00121

Gnomad AMR exome

AF:

0.00468

Gnomad ASJ exome

AF:

0.0547

Gnomad EAS exome

AF:

0.000332

Gnomad FIN exome

AF:

0.000339

Gnomad NFE exome

AF:

0.00318

Gnomad OTH exome

AF:

0.00785

GnomAD4 exome

AF:

0.00381

AC:

5559

AN:

1459280

Hom.:

Cov.:

AF XY:

0.00426

AC XY:

3089

AN XY:

725722

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

33438

American (AMR)

AF:

0.00433

AC:

191

AN:

44102

Ashkenazi Jewish (ASJ)

AF:

0.0528

AC:

1376

AN:

26064

East Asian (EAS)

AF:

0.000177

AC:

AN:

39592

South Asian (SAS)

AF:

0.0143

AC:

1231

AN:

85956

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

53248

Middle Eastern (MID)

AF:

0.0125

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00197

AC:

2189

AN:

1110818

Other (OTH)

AF:

0.00718

AC:

433

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

391

782

1173

1564

1955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

200

300

400

500

<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:

0.00349

AC:

531

AN:

152326

Hom.:

Cov.:

AF XY:

0.00365

AC XY:

272

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000914

AC:

AN:

41576

American (AMR)

AF:

0.00314

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0527

AC:

183

AN:

3472

East Asian (EAS)

AF:

0.000580

AC:

AN:

5176

South Asian (SAS)

AF:

0.0141

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00243

AC:

165

AN:

68026

Other (OTH)

AF:

0.00664

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00413

Hom.:

Bravo

AF:

0.00346

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hemochromatosis type 3

Benign:2Other:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

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. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

not provided

Benign:2

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TFR2: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary hemochromatosis

Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.38

(source)

DANN

Benign

0.68

PhyloP100

-4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.29

Position offset: -31

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