NM_003227.4:c.1127C>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003227.4(TFR2):c.1127C>A(p.Ala376Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 1,592,294 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0037 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 20 hom. )

Consequence

TFR2
NM_003227.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 2.54

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:

LOC124901709 (HGNC:):

LOC124901709 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00885278).

BP6

Variant 7-100631032-G-T is Benign according to our data. Variant chr7-100631032-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461196.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}. Variant chr7-100631032-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0037 (563/152326) while in subpopulation NFE AF= 0.00472 (321/68016). AF 95% confidence interval is 0.00429. There are 9 homozygotes in gnomad4. There are 256 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFR2	NM_003227.4 link	c.1127C>A	p.Ala376Asp	missense_variant	Exon 9 of 18	ENST00000223051.8	NP_003218.2	Q9UP52-1
TFR2	NM_001206855.3 link	c.614C>A	p.Ala205Asp	missense_variant	Exon 6 of 15		NP_001193784.1	Q9UP52-2
LOC124901709	XR_007060454.1 link	n.434-124G>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8 link	c.1127C>A	p.Ala376Asp	missense_variant	Exon 9 of 18	1	NM_003227.4	ENSP00000223051.3		Q9UP52-1

Frequencies

GnomAD3 genomes

AF:

0.00370

AC:

563

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.129

Gnomad AMR

AF:

0.00426

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00472

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00269

AC:

596

AN:

221158

Hom.:

AF XY:

0.00272

AC XY:

329

AN XY:

121060

show subpopulations

Gnomad AFR exome

AF:

0.000504

Gnomad AMR exome

AF:

0.00257

Gnomad ASJ exome

AF:

0.000120

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00166

Gnomad FIN exome

AF:

0.00156

Gnomad NFE exome

AF:

0.00416

Gnomad OTH exome

AF:

0.00357

GnomAD4 exome

AF:

0.00480

AC:

6917

AN:

1439968

Hom.:

Cov.:

AF XY:

0.00466

AC XY:

3339

AN XY:

715966

show subpopulations

Gnomad4 AFR exome

AF:

0.000713

Gnomad4 AMR exome

AF:

0.00229

Gnomad4 ASJ exome

AF:

0.0000808

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00149

Gnomad4 FIN exome

AF:

0.00172

Gnomad4 NFE exome

AF:

0.00575

Gnomad4 OTH exome

AF:

0.00402

GnomAD4 genome

AF:

0.00370

AC:

563

AN:

152326

Hom.:

Cov.:

AF XY:

0.00344

AC XY:

256

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000938

Gnomad4 AMR

AF:

0.00425

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.00472

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00433

Hom.:

Bravo

AF:

0.00396

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.000911

AC:

ESP6500EA

AF:

0.00420

AC:

ExAC

AF:

0.00255

AC:

309

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TFR2 p.A205D variant was not identified in the literature nor was it identified in Cosmic and LOVD 3.0. The variant was identified in dbSNP (ID: rs41303495) and in ClinVar (classified as likely benign by Invitae for associated condition of Hereditary Hemochromatosis). The variant was identified in control databases in 683 of 252548 chromosomes (3 homozygous) at a frequency of 0.002704 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 487 of 115588 chromosomes (freq: 0.004213), Other in 21 of 6406 chromosomes (freq: 0.003278), Latino in 76 of 30012 chromosomes (freq: 0.002532), South Asian in 46 of 27714 chromosomes (freq: 0.00166), European (Finnish) in 35 of 23298 chromosomes (freq: 0.001502), African in 17 of 22612 chromosomes (freq: 0.000752) and Ashkenazi Jewish in 1 of 8620 chromosomes (freq: 0.000116), but was not observed in the East Asian population. The p.Ala205 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TFR2: BP4, BS2 -

Hemochromatosis type 3

Uncertain:1Benign:1

Jan 09, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.47

T;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.71

T;.

M_CAP

Benign

0.022

MetaRNN

Benign

0.0089

T;T

MetaSVM

Benign

-0.71

MutationAssessor

Pathogenic

3.8

H;H

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.7

D;D

REVEL

Benign

0.20

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.92

P;P

Vest4

0.50

MVP

0.74

MPC

0.91

ClinPred

0.072

GERP RS

3.7

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.37

gMVP

0.84

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