7-100626830-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_003227.4(TFR2):​c.2069A>C​(p.Gln690Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000429 in 1,397,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

TFR2
NM_003227.4 missense

Scores

2
2
15

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 2.79

Publications

13 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: Likely_pathogenic. The variant received 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.967
PP5
Variant 7-100626830-T-G is Pathogenic according to our data. Variant chr7-100626830-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TFR2NM_003227.4 linkc.2069A>C p.Gln690Pro missense_variant Exon 17 of 18 ENST00000223051.8 NP_003218.2 Q9UP52-1
TFR2NM_001206855.3 linkc.1556A>C p.Gln519Pro missense_variant Exon 14 of 15 NP_001193784.1 Q9UP52-2
LOC124901709XR_007060454.1 linkn.433+4276T>G intron_variant Intron 1 of 2
LOC124901710XR_007060455.1 linkn.-80A>C upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TFR2ENST00000223051.8 linkc.2069A>C p.Gln690Pro missense_variant Exon 17 of 18 1 NM_003227.4 ENSP00000223051.3 Q9UP52-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000429
AC:
6
AN:
1397372
Hom.:
0
Cov.:
36
AF XY:
0.00000580
AC XY:
4
AN XY:
689376
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31592
American (AMR)
AF:
0.00
AC:
0
AN:
35730
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25166
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35734
South Asian (SAS)
AF:
0.0000379
AC:
3
AN:
79228
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
47438
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5548
European-Non Finnish (NFE)
AF:
9.27e-7
AC:
1
AN:
1078966
Other (OTH)
AF:
0.0000345
AC:
2
AN:
57970
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.458
Heterozygous variant carriers
0
1
2
3
4
5
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
Cov.:
33
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Hemochromatosis type 3 Pathogenic:1Other:1
-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Aug 01, 2002
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.67
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Benign
-0.090
CADD
Uncertain
25
DANN
Benign
0.96
DEOGEN2
Benign
0.36
T;T
Eigen
Benign
-0.22
Eigen_PC
Benign
-0.033
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Benign
0.68
T;.
M_CAP
Benign
0.071
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Benign
-0.87
T
MutationAssessor
Benign
0.90
L;L
PhyloP100
2.8
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-1.8
N;N
REVEL
Benign
0.21
Sift
Benign
0.17
T;T
Sift4G
Benign
0.14
T;T
Polyphen
0.21
B;B
Vest4
0.74
MutPred
0.81
Loss of MoRF binding (P = 0.0777);Loss of MoRF binding (P = 0.0777);
MVP
0.68
MPC
0.52
ClinPred
0.61
D
GERP RS
5.3
Varity_R
0.62
gMVP
0.87
Mutation Taster
=7/93
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: rs80338889; hg19: chr7-100224453; API