rs121908085
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_001206744.2(TPO):c.2395G>A(p.Glu799Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
TPO
NM_001206744.2 missense
NM_001206744.2 missense
Scores
9
8
2
Clinical Significance
Conservation
PhyloP100: 5.10
Genes affected
TPO (HGNC:12015): (thyroid peroxidase) This gene encodes a membrane-bound glycoprotein. The encoded protein acts as an enzyme and plays a central role in thyroid gland function. The protein functions in the iodination of tyrosine residues in thyroglobulin and phenoxy-ester formation between pairs of iodinated tyrosines to generate the thyroid hormones, thyroxine and triiodothyronine. Mutations in this gene are associated with several disorders of thyroid hormonogenesis, including congenital hypothyroidism, congenital goiter, and thyroid hormone organification defect IIA. Multiple transcript variants encoding distinct isoforms have been identified for this gene, but the full-length nature of some variants has not been determined. [provided by RefSeq, May 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
?
In a domain EGF-like; calcium-binding (size 43) in uniprot entity PERT_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001206744.2
PM2
?
Very rare variant in population databases, with high coverage;
PP3
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MetaRNN computational evidence supports a deleterious effect, 0.921
PP5
?
Variant 2-1503956-G-A is Pathogenic according to our data. Variant chr2-1503956-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPO | NM_001206744.2 | c.2395G>A | p.Glu799Lys | missense_variant | 14/17 | ENST00000329066.9 | |
LOC124905966 | XR_007086185.1 | n.167-17765C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPO | ENST00000329066.9 | c.2395G>A | p.Glu799Lys | missense_variant | 14/17 | 1 | NM_001206744.2 | P1 | |
ENST00000650512.1 | n.547+76245C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152136Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251310Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135862
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GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461870Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727238
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152254Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74452
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Deficiency of iodide peroxidase Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1999 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital | Feb 20, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The TPO c.2395G>A (p.Glu799Lys) variant has been reported in three studies in a total of 17 individuals with congenital hypothyroidism, including 11 homozygotes from a large consanguineous Amish family where the variant co-segregated with disease and six unrelated compound heterozygotes (Bikker et al. 1995; Pannain et al. 1999; Avbelj et al. 2007). Control data are unavailable for the variant, which is reported at a frequency of 0.00485 in the Chinese Han in Beijing, China, population of the 1000 Genomes Project, however this is based on one allele only so the variant is presumed to be rare. In CHO-K1 cells, the p.Glu799Lys variant had similar cellular distribution and expression levels compared to wildtype but had non-detectable activity in the guaiacol assay and exhibited nonenzymatic reaction rate in iodide oxidation assay, suggesting that this variant produces inactive TPO (Bikker et al. 1997). Based on the evidence, the p.Glu799Lys variant is classified as pathogenic for congenital hypothyroidism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 799 of the TPO protein (p.Glu799Lys). This variant is present in population databases (rs121908085, gnomAD 0.0009%). This missense change has been observed in individual(s) with thyroid dyshormonogenesis (PMID: 7550241, 28444304, 34780050). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.2485G>A. ClinVar contains an entry for this variant (Variation ID: 4046). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Pathogenic
D;D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;.;.
MutationTaster
Benign
A;A;A;A;A;A;A
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at