chr3-133777188-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_001063.4(TF):c.2012G>A(p.Gly671Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00385 in 1,614,010 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 14 hom. )

Consequence

TF
NM_001063.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts P:1B:6

Conservation

PhyloP100: 5.21

Publications

16 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=0.01994747).

BP6

Variant 3-133777188-G-A is Benign according to our data. Variant chr3-133777188-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 12616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00294 (448/152282) while in subpopulation NFE AF = 0.00507 (345/68016). AF 95% confidence interval is 0.00463. There are 3 homozygotes in GnomAd4. There are 190 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TF	NM_001063.4 link	c.2012G>A	p.Gly671Glu	missense_variant	Exon 16 of 17	ENST00000402696.9	NP_001054.2
TF	NM_001354703.2 link	c.1880G>A	p.Gly627Glu	missense_variant	Exon 22 of 23		NP_001341632.2
TF	NM_001354704.2 link	c.1631G>A	p.Gly544Glu	missense_variant	Exon 15 of 16		NP_001341633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TF	ENST00000402696.9 link	c.2012G>A	p.Gly671Glu	missense_variant	Exon 16 of 17	1	NM_001063.4	ENSP00000385834.3
TF	ENST00000467842.1 link	n.3006G>A		non_coding_transcript_exon_variant	Exon 2 of 2	1
TF	ENST00000461695.1 link	n.*312G>A		non_coding_transcript_exon_variant	Exon 6 of 7	3		ENSP00000419714.1
TF	ENST00000461695.1 link	n.*312G>A		3_prime_UTR_variant	Exon 6 of 7	3		ENSP00000419714.1

Frequencies

GnomAD3 genomes

AF:

0.00294

AC:

448

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00507

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00251

AC:

630

AN:

251236

AF XY:

0.00260

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000745

Gnomad NFE exome

AF:

0.00429

Gnomad OTH exome

AF:

0.00424

GnomAD4 exome

AF:

0.00395

AC:

5772

AN:

1461728

Hom.:

Cov.:

AF XY:

0.00387

AC XY:

2813

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33480

American (AMR)

AF:

0.00201

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000612

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.000313

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000788

AC:

AN:

53274

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00485

AC:

5397

AN:

1111996

Other (OTH)

AF:

0.00286

AC:

173

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

315

630

944

1259

1574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

198

396

594

792

990

<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:

0.00294

AC:

448

AN:

152282

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

190

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41544

American (AMR)

AF:

0.00176

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00507

AC:

345

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00394

Hom.:

Bravo

AF:

0.00275

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00250

AC:

303

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00442

EpiControl

AF:

0.00462

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Atransferrinemia

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Dec 31, 2023

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TF: BS1

Transferrin variant B2

Pathogenic:1

May 01, 1984

OMIM

Significance:Pathogenic

Review Status:flagged submission

Collection Method:literature only

not specified

Benign:1

Feb 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TF c.2012G>A (p.Gly671Glu) results in a non-conservative amino acid change located in the Transferrin-like domain of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 251236 control chromosomes. The observed variant frequency is approximately 2.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in TF causing Atransferrinemia phenotype (0.0011), strongly suggesting that the variant is benign. c.2012G>A has been reported in the literature, without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Atransferrinemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two submitters classified the variant as likely benign while one classified as pathogneic. Based on the evidence outlined above, the variant was classified as likely benign.

TF-related disorder

Benign:1

Jan 26, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.020

MetaSVM

Uncertain

0.042

MutationAssessor

Pathogenic

4.5

PhyloP100

5.2

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-6.8

REVEL

Uncertain

0.39

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Vest4

0.63

ClinPred

0.15

GERP RS

5.5

Varity_R

0.94

gMVP

0.83

Mutation Taster

=23/77

disease causing

(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