rs121918677

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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 -16 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 id is 12616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-133777188-G-A is described in Lovd as [Pathogenic].

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TF	NM_001063.4 linkuse as main transcript	c.2012G>A	p.Gly671Glu	missense_variant	16/17	ENST00000402696.9
TF	NM_001354703.2 linkuse as main transcript	c.1880G>A	p.Gly627Glu	missense_variant	22/23
TF	NM_001354704.2 linkuse as main transcript	c.1631G>A	p.Gly544Glu	missense_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TF	ENST00000402696.9 linkuse as main transcript	c.2012G>A	p.Gly671Glu	missense_variant	16/17	1	NM_001063.4	P1
TF	ENST00000467842.1 linkuse as main transcript	n.3006G>A		non_coding_transcript_exon_variant	2/2	1
TF	ENST00000461695.1 linkuse as main transcript	c.*312G>A		3_prime_UTR_variant, NMD_transcript_variant	6/7	3

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

GnomAD3 exomes

AF:

0.00251

AC:

630

AN:

251236

Hom.:

AF XY:

0.00260

AC XY:

353

AN XY:

135816

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 SAS exome

AF:

0.000425

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

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.00201

Gnomad4 ASJ exome

AF:

0.000612

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.000788

Gnomad4 NFE exome

AF:

0.00485

Gnomad4 OTH exome

AF:

0.00286

GnomAD4 genome

AF:

0.00294

AC:

448

AN:

152282

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

190

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00101

Gnomad4 AMR

AF:

0.00176

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.00507

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00412

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

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Dec 31, 2023	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	TF: BS1 -

Transferrin variant B2

Pathogenic:1

Pathogenic, flagged submission

literature only

OMIM

May 01, 1984

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 15, 2023

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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 26, 2024

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

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

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-6.8

REVEL

Uncertain

0.39

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.63

MVP

0.86

MPC

1.2

ClinPred

0.15

GERP RS

5.5

Varity_R

0.94

gMVP

0.83

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