3-133756943-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001063.4(TF):c.804T>C(p.His268His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,614,086 control chromosomes in the GnomAD database, including 1,369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.054 ( 714 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 655 hom. )

Consequence

TF
NM_001063.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.54

Publications

5 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 3-133756943-T-C is Benign according to our data. Variant chr3-133756943-T-C is described in ClinVar as Benign. ClinVar VariationId is 343440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.54 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TF	NM_001063.4 link	c.804T>C	p.His268His	synonymous_variant	Exon 7 of 17	ENST00000402696.9	NP_001054.2	P02787Q06AH7A0PJA6
TF	NM_001354703.2 link	c.672T>C	p.His224His	synonymous_variant	Exon 13 of 23		NP_001341632.2
TF	NM_001354704.2 link	c.423T>C	p.His141His	synonymous_variant	Exon 6 of 16		NP_001341633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TF	ENST00000402696.9 link	c.804T>C	p.His268His	synonymous_variant	Exon 7 of 17	1	NM_001063.4	ENSP00000385834.3	P02787
TF	ENST00000485977.1 link	n.169T>C		non_coding_transcript_exon_variant	Exon 3 of 5	3		ENSP00000418716.1	F8WC57
TF	ENST00000482271.5 link	c.*20T>C		downstream_gene_variant		4		ENSP00000419338.1	C9JVG0

Frequencies

GnomAD3 genomes

AF:

0.0538

AC:

8191

AN:

152130

Hom.:

712

Cov.:

show subpopulations

Gnomad AFR

AF:

0.187

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0217

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.0359

GnomAD2 exomes

AF:

0.0142

AC:

3566

AN:

251434

AF XY:

0.0102

show subpopulations

Gnomad AFR exome

AF:

0.192

Gnomad AMR exome

AF:

0.00968

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000484

Gnomad OTH exome

AF:

0.00619

GnomAD4 exome

AF:

0.00558

AC:

8164

AN:

1461838

Hom.:

655

Cov.:

AF XY:

0.00483

AC XY:

3509

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.193

AC:

6458

AN:

33480

American (AMR)

AF:

0.0111

AC:

496

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000421

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000325

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00884

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000335

AC:

373

AN:

1111970

Other (OTH)

AF:

0.0124

AC:

747

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

439

878

1318

1757

2196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

392

588

784

980

<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:

0.0539

AC:

8203

AN:

152248

Hom.:

714

Cov.:

AF XY:

0.0523

AC XY:

3897

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.186

AC:

7740

AN:

41522

American (AMR)

AF:

0.0216

AC:

331

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000735

AC:

AN:

68018

Other (OTH)

AF:

0.0355

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

325

650

974

1299

1624

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0277

Hom.:

331

Bravo

AF:

0.0611

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 27, 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

- -

Atransferrinemia

Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.21

(source)

DANN

Benign

0.55

PhyloP100

-1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

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