rs80338882

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_003227.4(TFR2):​c.1186C>T​(p.Arg396*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,612,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R396R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

TFR2
NM_003227.4 stop_gained

Scores

1
6

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: -0.415

Publications

10 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-100630973-G-A is Pathogenic according to our data. Variant chr7-100630973-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 21362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TFR2NM_003227.4 linkc.1186C>T p.Arg396* stop_gained Exon 9 of 18 ENST00000223051.8 NP_003218.2 Q9UP52-1
TFR2NM_001206855.3 linkc.673C>T p.Arg225* stop_gained Exon 6 of 15 NP_001193784.1 Q9UP52-2
LOC124901709XR_007060454.1 linkn.434-183G>A intron_variant Intron 1 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TFR2ENST00000223051.8 linkc.1186C>T p.Arg396* stop_gained Exon 9 of 18 1 NM_003227.4 ENSP00000223051.3 Q9UP52-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152186
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000400
AC:
1
AN:
250226
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000885
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1460388
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
726446
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33444
American (AMR)
AF:
0.00
AC:
0
AN:
44642
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26100
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39696
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86152
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53374
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5046
European-Non Finnish (NFE)
AF:
0.00000810
AC:
9
AN:
1111664
Other (OTH)
AF:
0.0000332
AC:
2
AN:
60270
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.530
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000131
AC:
2
AN:
152186
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74334
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41454
American (AMR)
AF:
0.0000655
AC:
1
AN:
15266
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68036
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000310
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hemochromatosis type 3 Pathogenic:2Other:1
Jun 09, 2020
Natera, Inc.
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Oct 27, 2023
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Hereditary hemochromatosis Pathogenic:1
Oct 29, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg396*) in the TFR2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TFR2 are known to be pathogenic (PMID: 23600741, 26029709). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with hemochromatosis (PMID: 16424658, 18450729). ClinVar contains an entry for this variant (Variation ID: 21362). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Benign
-0.35
CADD
Pathogenic
27
DANN
Benign
0.80
Eigen
Benign
-0.35
Eigen_PC
Benign
-0.67
FATHMM_MKL
Benign
0.020
N
PhyloP100
-0.41
Vest4
0.79
ClinPred
0.18
T
GERP RS
0.66
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=17/183
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80338882; hg19: chr7-100228596; COSMIC: COSV99774512; COSMIC: COSV99774512; API