7-100629279-C-T

Position:

chr7-100629279-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_003227.4(TFR2):c.1364G>A(p.Arg455Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,614,034 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 5 hom. )

Consequence

TFR2
NM_003227.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4O:2

Conservation

PhyloP100: 2.53

Variant links:

Genes affected

TFR2 (HGNC:11762): (transferrin receptor 2) This gene encodes a single-pass type II membrane protein, which is a member of the transferrin receptor-like family. This protein mediates cellular uptake of transferrin-bound iron, and may be involved in iron metabolism, hepatocyte function and erythrocyte differentiation. Mutations in this gene have been associated with hereditary hemochromatosis type III. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, May 2011]

TFR2 links:

TFR2 (HGNC:):

TFR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02515769).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00209 (318/152328) while in subpopulation NFE AF= 0.00344 (234/68028). AF 95% confidence interval is 0.00308. There are 0 homozygotes in gnomad4. There are 145 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFR2	NM_003227.4 linkuse as main transcript	c.1364G>A	p.Arg455Gln	missense_variant	10/18	ENST00000223051.8	NP_003218.2	Q9UP52-1
TFR2	NM_001206855.3 linkuse as main transcript	c.851G>A	p.Arg284Gln	missense_variant	7/15		NP_001193784.1	Q9UP52-2
LOC124901709	XR_007060454.1 linkuse as main transcript	n.434-1877C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8 linkuse as main transcript	c.1364G>A	p.Arg455Gln	missense_variant	10/18	1	NM_003227.4	ENSP00000223051.3		Q9UP52-1

Frequencies

GnomAD3 genomes

AF:

0.00209

AC:

318

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00358

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00344

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00194

AC:

489

AN:

251440

Hom.:

AF XY:

0.00194

AC XY:

263

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000555

Gnomad FIN exome

AF:

0.00337

Gnomad NFE exome

AF:

0.00325

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00310

AC:

4538

AN:

1461706

Hom.:

Cov.:

AF XY:

0.00303

AC XY:

2203

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000522

Gnomad4 FIN exome

AF:

0.00384

Gnomad4 NFE exome

AF:

0.00371

Gnomad4 OTH exome

AF:

0.00212

GnomAD4 genome

AF:

0.00209

AC:

318

AN:

152328

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

145

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00358

Gnomad4 NFE

AF:

0.00344

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00292

Hom.:

Bravo

AF:

0.00160

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00203

AC:

247

EpiCase

AF:

0.00278

EpiControl

AF:

0.00332

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hemochromatosis type 3

Uncertain:1Benign:1Other:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 16, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary hemochromatosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2019

- -

TFR2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 09, 2020

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). -

Hemochromatosis, type 1, modifier of

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;T

Eigen

Benign

-0.032

Eigen_PC

Benign

-0.072

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.81

T;.

M_CAP

Benign

0.016

MetaRNN

Benign

0.025

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.16

Sift

Benign

0.33

T;T

Sift4G

Benign

0.15

T;T

Polyphen

0.84

P;P

Vest4

0.49

MVP

0.64

MPC

0.55

ClinPred

0.017

GERP RS

3.5

Varity_R

0.23

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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