3-133775510-C-T

Position:

chr3-133775510-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 12617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-133775510-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein
TF	NM_001063.4 linkuse as main transcript	c.1765C>T	p.Pro589Ser	missense_variant	15/17	ENST00000402696.9	NP_001054.2
TF	NM_001354703.2 linkuse as main transcript	c.1633C>T	p.Pro545Ser	missense_variant	21/23		NP_001341632.2
TF	NM_001354704.2 linkuse as main transcript	c.1384C>T	p.Pro462Ser	missense_variant	14/16		NP_001341633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TF	ENST00000402696.9 linkuse as main transcript	c.1765C>T	p.Pro589Ser	missense_variant	15/17	1	NM_001063.4	ENSP00000385834	P1
TF	ENST00000467842.1 linkuse as main transcript	n.2759C>T		non_coding_transcript_exon_variant	1/2	1
TF	ENST00000461695.1 linkuse as main transcript	c.*65C>T		3_prime_UTR_variant, NMD_transcript_variant	5/7	3		ENSP00000419714

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

GnomAD3 exomes

AF:

0.160

AC:

40310

AN:

251486

Hom.:

3586

AF XY:

0.165

AC XY:

22478

AN XY:

135918

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 SAS exome

AF:

0.212

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

Gnomad4 AFR exome

AF:

0.0803

Gnomad4 AMR exome

AF:

0.123

Gnomad4 ASJ exome

AF:

0.210

Gnomad4 EAS exome

AF:

0.245

Gnomad4 SAS exome

AF:

0.212

Gnomad4 FIN exome

AF:

0.111

Gnomad4 NFE exome

AF:

0.163

Gnomad4 OTH exome

AF:

0.171

GnomAD4 genome

AF:

0.138

AC:

20991

AN:

152206

Hom.:

1644

Cov.:

AF XY:

0.139

AC XY:

10343

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0757

Gnomad4 AMR

AF:

0.148

Gnomad4 ASJ

AF:

0.215

Gnomad4 EAS

AF:

0.253

Gnomad4 SAS

AF:

0.220

Gnomad4 FIN

AF:

0.102

Gnomad4 NFE

AF:

0.159

Gnomad4 OTH

AF:

0.158

Alfa

AF:

0.161

Hom.:

4243

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

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 25, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

TF*C2

Other:1

association, no assertion criteria provided

literature only

OMIM

Jan 02, 2024

- -

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

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

MutationTaster

Benign

1.0

P;P

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over