rs34242818

Positions:

chr7-100633241-G-C

Variant summary

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

The NM_003227.4(TFR2):c.714C>G(p.Ile238Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00989 in 1,613,732 control chromosomes in the GnomAD database, including 733 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 331 hom., cov: 30)

Exomes 𝑓: 0.0069 ( 402 hom. )

Consequence

TFR2
NM_003227.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -5.23

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:

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=0.001814574).

BP6

Variant 7-100633241-G-C is Benign according to our data. Variant chr7-100633241-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 21378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-100633241-G-C is described in Lovd as [Benign]. Variant chr7-100633241-G-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFR2	NM_003227.4 link	c.714C>G	p.Ile238Met	missense_variant	5/18	ENST00000223051.8	NP_003218.2	Q9UP52-1
TFR2	NM_001206855.3 link	c.201C>G	p.Ile67Met	missense_variant	2/15		NP_001193784.1	Q9UP52-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8 link	c.714C>G	p.Ile238Met	missense_variant	5/18	1	NM_003227.4	ENSP00000223051.3		Q9UP52-1

Frequencies

GnomAD3 genomes

AF:

0.0382

AC:

5811

AN:

152102

Hom.:

329

Cov.:

show subpopulations

Gnomad AFR

AF:

0.122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0108

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0625

Gnomad SAS

AF:

0.0284

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.0258

GnomAD3 exomes

AF:

0.0177

AC:

4398

AN:

248788

Hom.:

164

AF XY:

0.0161

AC XY:

2180

AN XY:

135008

show subpopulations

Gnomad AFR exome

AF:

0.125

Gnomad AMR exome

AF:

0.00797

Gnomad ASJ exome

AF:

0.000299

Gnomad EAS exome

AF:

0.0646

Gnomad SAS exome

AF:

0.0274

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000784

Gnomad OTH exome

AF:

0.00987

GnomAD4 exome

AF:

0.00694

AC:

10147

AN:

1461512

Hom.:

402

Cov.:

AF XY:

0.00717

AC XY:

5212

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.125

Gnomad4 AMR exome

AF:

0.00834

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0554

Gnomad4 SAS exome

AF:

0.0242

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000463

Gnomad4 OTH exome

AF:

0.0120

GnomAD4 genome

AF:

0.0382

AC:

5811

AN:

152220

Hom.:

331

Cov.:

AF XY:

0.0374

AC XY:

2785

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.122

Gnomad4 AMR

AF:

0.0108

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0618

Gnomad4 SAS

AF:

0.0284

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000838

Gnomad4 OTH

AF:

0.0255

Alfa

AF:

0.00741

Hom.:

Bravo

AF:

0.0420

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.125

AC:

550

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0202

AC:

2450

Asia WGS

AF:

0.0340

AC:

118

AN:

3478

EpiCase

AF:

0.00131

EpiControl

AF:

0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hemochromatosis type 3

Benign:2Other:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 08, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2020	This variant is associated with the following publications: (PMID: 30998180) -

Hereditary hemochromatosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.47

DANN

Benign

0.97

DEOGEN2

Benign

0.079

T;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.71

T;T;.

MetaRNN

Benign

0.0018

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.90

L;.;L

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.010

N;N;N

REVEL

Benign

0.061

Sift

Uncertain

0.010

D;T;D

Sift4G

Uncertain

0.028

D;T;D

Polyphen

0.43

B;.;B

Vest4

0.089

MPC

0.80

ClinPred

0.033

GERP RS

-12

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.0

Varity_R

0.15

gMVP

0.46

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