rs41295942

Positions:

chr7-100621008-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003227.4(TFR2):c.2255G>A(p.Arg752His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0267 in 1,603,208 control chromosomes in the GnomAD database, including 683 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 48 hom., cov: 32)

Exomes 𝑓: 0.027 ( 635 hom. )

Consequence

TFR2
NM_003227.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.659

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=0.005874753).

BP6

Variant 7-100621008-C-T is Benign according to our data. Variant chr7-100621008-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 221188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-100621008-C-T is described in Lovd as [Benign]. Variant chr7-100621008-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0212 (3222/152314) while in subpopulation NFE AF= 0.033 (2244/68016). AF 95% confidence interval is 0.0319. There are 48 homozygotes in gnomad4. There are 1509 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 48 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFR2	NM_003227.4 link	c.2255G>A	p.Arg752His	missense_variant	18/18	ENST00000223051.8	NP_003218.2	Q9UP52-1
TFR2	NM_001206855.3 link	c.1742G>A	p.Arg581His	missense_variant	15/15		NP_001193784.1	Q9UP52-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8 link	c.2255G>A	p.Arg752His	missense_variant	18/18	1	NM_003227.4	ENSP00000223051.3		Q9UP52-1

Frequencies

GnomAD3 genomes

AF:

0.0212

AC:

3223

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00468

Gnomad AMI

AF:

0.0548

Gnomad AMR

AF:

0.0180

Gnomad ASJ

AF:

0.0207

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00724

Gnomad FIN

AF:

0.0289

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0330

Gnomad OTH

AF:

0.0205

GnomAD3 exomes

AF:

0.0205

AC:

4645

AN:

226790

Hom.:

AF XY:

0.0209

AC XY:

2569

AN XY:

123166

show subpopulations

Gnomad AFR exome

AF:

0.00400

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00925

Gnomad FIN exome

AF:

0.0304

Gnomad NFE exome

AF:

0.0303

Gnomad OTH exome

AF:

0.0228

GnomAD4 exome

AF:

0.0272

AC:

39531

AN:

1450894

Hom.:

635

Cov.:

AF XY:

0.0269

AC XY:

19399

AN XY:

720882

show subpopulations

Gnomad4 AFR exome

AF:

0.00428

Gnomad4 AMR exome

AF:

0.0116

Gnomad4 ASJ exome

AF:

0.0195

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.0100

Gnomad4 FIN exome

AF:

0.0322

Gnomad4 NFE exome

AF:

0.0311

Gnomad4 OTH exome

AF:

0.0232

GnomAD4 genome

AF:

0.0212

AC:

3222

AN:

152314

Hom.:

Cov.:

AF XY:

0.0203

AC XY:

1509

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00467

Gnomad4 AMR

AF:

0.0180

Gnomad4 ASJ

AF:

0.0207

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00704

Gnomad4 FIN

AF:

0.0289

Gnomad4 NFE

AF:

0.0330

Gnomad4 OTH

AF:

0.0203

Alfa

AF:

0.0276

Hom.:

Bravo

AF:

0.0188

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0275

AC:

106

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0281

AC:

241

ExAC

AF:

0.0190

AC:

2303

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hemochromatosis type 3

Benign:2

Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Hereditary hemochromatosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

T;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.78

T;.

MetaRNN

Benign

0.0059

T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.18

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.024

D;D

Polyphen

1.0

D;D

Vest4

0.13

MPC

1.2

ClinPred

0.020

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

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