3-133775510-C-T

Variant names:

Variant summary

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

The NM_001063.4(TF):c.1765C>T(p.Pro589Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,613,992 control chromosomes in the GnomAD database, including 22,356 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1644 hom., cov: 32)

Exomes 𝑓: 0.16 ( 20712 hom. )

Consequence

TF
NM_001063.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: -2.25

Publications

107 publications found

Variant links:

Genes affected

TF (HGNC:11740): (transferrin) This gene encodes a glycoprotein with an approximate molecular weight of 76.5 kDa. It is thought to have been created as a result of an ancient gene duplication event that led to generation of homologous C and N-terminal domains each of which binds one ion of ferric iron. The function of this protein is to transport iron from the intestine, reticuloendothelial system, and liver parenchymal cells to all proliferating cells in the body. This protein may also have a physiologic role as granulocyte/pollen-binding protein (GPBP) involved in the removal of certain organic matter and allergens from serum. [provided by RefSeq, Sep 2009]

TF Gene-Disease associations (from GenCC):

atransferrinemia
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp

TF 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=0.0067822933).

BP6

Variant 3-133775510-C-T is Benign according to our data. Variant chr3-133775510-C-T is described in ClinVar as Benign. ClinVar VariationId is 12617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TF	NM_001063.4 link	c.1765C>T	p.Pro589Ser	missense_variant	Exon 15 of 17	ENST00000402696.9	NP_001054.2
TF	NM_001354703.2 link	c.1633C>T	p.Pro545Ser	missense_variant	Exon 21 of 23		NP_001341632.2
TF	NM_001354704.2 link	c.1384C>T	p.Pro462Ser	missense_variant	Exon 14 of 16		NP_001341633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TF	ENST00000402696.9 link	c.1765C>T	p.Pro589Ser	missense_variant	Exon 15 of 17	1	NM_001063.4	ENSP00000385834.3
TF	ENST00000467842.1 link	n.2759C>T		non_coding_transcript_exon_variant	Exon 1 of 2	1
TF	ENST00000461695.1 link	n.*65C>T		non_coding_transcript_exon_variant	Exon 5 of 7	3		ENSP00000419714.1
TF	ENST00000461695.1 link	n.*65C>T		3_prime_UTR_variant	Exon 5 of 7	3		ENSP00000419714.1

Frequencies

GnomAD3 genomes

AF:

0.138

AC:

20988

AN:

152086

Hom.:

1644

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0758

Gnomad AMI

AF:

0.177

Gnomad AMR

AF:

0.148

Gnomad ASJ

AF:

0.215

Gnomad EAS

AF:

0.252

Gnomad SAS

AF:

0.219

Gnomad FIN

AF:

0.102

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.159

Gnomad OTH

AF:

0.161

GnomAD2 exomes

AF:

0.160

AC:

40310

AN:

251486

AF XY:

0.165

show subpopulations

Gnomad AFR exome

AF:

0.0710

Gnomad AMR exome

AF:

0.119

Gnomad ASJ exome

AF:

0.212

Gnomad EAS exome

AF:

0.261

Gnomad FIN exome

AF:

0.106

Gnomad NFE exome

AF:

0.160

Gnomad OTH exome

AF:

0.173

GnomAD4 exome

AF:

0.165

AC:

240815

AN:

1461786

Hom.:

20712

Cov.:

AF XY:

0.167

AC XY:

121364

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0803

AC:

2688

AN:

33480

American (AMR)

AF:

0.123

AC:

5480

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.210

AC:

5501

AN:

26136

East Asian (EAS)

AF:

0.245

AC:

9733

AN:

39698

South Asian (SAS)

AF:

0.212

AC:

18326

AN:

86254

European-Finnish (FIN)

AF:

0.111

AC:

5917

AN:

53416

Middle Eastern (MID)

AF:

0.218

AC:

1258

AN:

5768

European-Non Finnish (NFE)

AF:

0.163

AC:

181613

AN:

1111926

Other (OTH)

AF:

0.171

AC:

10299

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

11742

23483

35225

46966

58708

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6592

13184

19776

26368

32960

<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:

0.138

AC:

20991

AN:

152206

Hom.:

1644

Cov.:

AF XY:

0.139

AC XY:

10343

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0757

AC:

3145

AN:

41536

American (AMR)

AF:

0.148

AC:

2262

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.215

AC:

747

AN:

3468

East Asian (EAS)

AF:

0.253

AC:

1306

AN:

5166

South Asian (SAS)

AF:

0.220

AC:

1061

AN:

4822

European-Finnish (FIN)

AF:

0.102

AC:

1084

AN:

10598

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.159

AC:

10831

AN:

68004

Other (OTH)

AF:

0.158

AC:

335

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

939

1877

2816

3754

4693

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

234

468

702

936

1170

<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:

0.157

Hom.:

7801

Bravo

AF:

0.138

TwinsUK

AF:

0.162

AC:

601

ALSPAC

AF:

0.163

AC:

627

ESP6500AA

AF:

0.0769

AC:

339

ESP6500EA

AF:

0.158

AC:

1358

ExAC

AF:

0.160

AC:

19445

Asia WGS

AF:

0.195

AC:

681

AN:

3478

EpiCase

AF:

0.168

EpiControl

AF:

0.174

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Atransferrinemia

Benign:2

Mar 25, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 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 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

TF*C2

Other:1

Jan 02, 2024

OMIM

Significance:association

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.0010

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.41

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0068

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.2

PhyloP100

-2.3

PrimateAI

Benign

0.27

PROVEAN

Pathogenic

-5.9

REVEL

Benign

0.041

Sift

Benign

0.11

Sift4G

Benign

0.19

Polyphen

0.0020

Vest4

0.031

MPC

0.34

ClinPred

0.015

GERP RS

-6.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.44

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over