dbSNP rs202221581: TFR2:p.Gly373Val (chr7-100631041-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_003227.4(TFR2):c.1118G>T(p.Gly373Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000126 in 1,583,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G373D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

TFR2
NM_003227.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.37

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

hemochromatosis type 3
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

TFR2 links:

LOC124901709 (HGNC:):

LOC124901709 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TFR2	NM_003227.4 link	c.1118G>T	p.Gly373Val	missense_variant	Exon 9 of 18	ENST00000223051.8	NP_003218.2
TFR2	NM_001206855.3 link	c.605G>T	p.Gly202Val	missense_variant	Exon 6 of 15		NP_001193784.1
LOC124901709	XR_007060454.1 link	n.434-115C>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8 link	c.1118G>T	p.Gly373Val	missense_variant	Exon 9 of 18	1	NM_003227.4	ENSP00000223051.3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.99e-7

AC:

AN:

1431362

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

711194

show subpopulations

African (AFR)

AF:

0.0000314

AC:

AN:

31806

American (AMR)

AF:

0.00

AC:

AN:

37328

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24202

East Asian (EAS)

AF:

0.00

AC:

AN:

39400

South Asian (SAS)

AF:

0.00

AC:

AN:

82494

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51984

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4944

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100298

Other (OTH)

AF:

0.00

AC:

AN:

58906

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Benign

0.94

DEOGEN2

Uncertain

0.67

D;D

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

T;.

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Pathogenic

4.2

H;H

PhyloP100

5.4

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-7.2

D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.76

MutPred

0.40

Loss of disorder (P = 0.0429);Loss of disorder (P = 0.0429);

MVP

0.78

MPC

1.2

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.83

gMVP

0.91

Mutation Taster

=25/75

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over