3-133756968-G-A

Position:

chr3-133756968-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001063.4(TF):c.829G>A(p.Gly277Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0488 in 1,614,076 control chromosomes in the GnomAD database, including 2,443 homozygotes. In-silico tool predicts 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 0.045 ( 273 hom., cov: 32)

Exomes 𝑓: 0.049 ( 2170 hom. )

Consequence

TF
NM_001063.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.28

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=0.0019334853).

BP6

Variant 3-133756968-G-A is Benign according to our data. Variant chr3-133756968-G-A is described in ClinVar as [Benign]. Clinvar id is 12622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TF	NM_001063.4 linkuse as main transcript	c.829G>A	p.Gly277Ser	missense_variant	7/17	ENST00000402696.9	NP_001054.2	P02787Q06AH7A0PJA6
TF	NM_001354703.2 linkuse as main transcript	c.697G>A	p.Gly233Ser	missense_variant	13/23		NP_001341632.2
TF	NM_001354704.2 linkuse as main transcript	c.448G>A	p.Gly150Ser	missense_variant	6/16		NP_001341633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TF	ENST00000402696.9 linkuse as main transcript	c.829G>A	p.Gly277Ser	missense_variant	7/17	1	NM_001063.4	ENSP00000385834.3	P02787
TF	ENST00000485977.1 linkuse as main transcript	n.194G>A		non_coding_transcript_exon_variant	3/5	3		ENSP00000418716.1	F8WC57
TF	ENST00000482271.5 linkuse as main transcript	c.*45G>A		downstream_gene_variant		4		ENSP00000419338.1	C9JVG0

Frequencies

GnomAD3 genomes

AF:

0.0449

AC:

6832

AN:

152086

Hom.:

273

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00845

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.0347

Gnomad ASJ

AF:

0.0616

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0452

Gnomad FIN

AF:

0.153

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0558

Gnomad OTH

AF:

0.0407

GnomAD3 exomes

AF:

0.0524

AC:

13161

AN:

251324

Hom.:

525

AF XY:

0.0541

AC XY:

7355

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00904

Gnomad AMR exome

AF:

0.0243

Gnomad ASJ exome

AF:

0.0597

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0467

Gnomad FIN exome

AF:

0.146

Gnomad NFE exome

AF:

0.0585

Gnomad OTH exome

AF:

0.0534

GnomAD4 exome

AF:

0.0492

AC:

71868

AN:

1461872

Hom.:

2170

Cov.:

AF XY:

0.0494

AC XY:

35896

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00899

Gnomad4 AMR exome

AF:

0.0269

Gnomad4 ASJ exome

AF:

0.0621

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0466

Gnomad4 FIN exome

AF:

0.143

Gnomad4 NFE exome

AF:

0.0485

Gnomad4 OTH exome

AF:

0.0468

GnomAD4 genome

AF:

0.0449

AC:

6833

AN:

152204

Hom.:

273

Cov.:

AF XY:

0.0487

AC XY:

3623

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.00845

Gnomad4 AMR

AF:

0.0347

Gnomad4 ASJ

AF:

0.0616

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0456

Gnomad4 FIN

AF:

0.153

Gnomad4 NFE

AF:

0.0558

Gnomad4 OTH

AF:

0.0403

Alfa

AF:

0.0499

Hom.:

404

Bravo

AF:

0.0337

TwinsUK

AF:

0.0456

AC:

169

ALSPAC

AF:

0.0485

AC:

187

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.0476

AC:

409

ExAC

AF:

0.0532

AC:

6456

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0547

EpiControl

AF:

0.0538

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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	-	- -

Iron deficiency anemia

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Jan 01, 2006

- -

Atransferrinemia

Benign:1

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. -

TF-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2023

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

Benign

0.13

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.7

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-4.2

REVEL

Benign

0.16

Sift

Benign

0.040

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.032

MPC

1.1

ClinPred

0.020

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.62

gMVP

0.35

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