chr1-53904716-A-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 8P and 6B. PVS1BP6_ModerateBS2
The ENST00000524406.5(DIO1):c.1A>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,894 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 Likely benign (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
DIO1
ENST00000524406.5 start_lost
ENST00000524406.5 start_lost
Scores
14
Clinical Significance
Conservation
PhyloP100: 1.16
Genes affected
DIO1 (HGNC:2883): (iodothyronine deiodinase 1) The protein encoded by this gene belongs to the iodothyronine deiodinase family. It catalyzes the activation, as well as the inactivation of thyroid hormone by outer and inner ring deiodination, respectively. The activation reaction involves the conversion of the prohormone thyroxine (3,5,3',5'-tetraiodothyronine, T4), secreted by the thyroid gland, to the bioactive thyroid hormone (3,5,3'-triiodothyronine, T3) by 5'-deiodination. This protein provides most of the circulating T3, which is essential for growth, differentiation and basal metabolism in vertebrates. This protein is a selenoprotein, containing the rare amino acid selenocysteine (Sec) at its active site. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2018]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
BP6
?
Variant 1-53904716-A-C is Benign according to our data. Variant chr1-53904716-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2298038.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
?
High AC in GnomAdExome at 12 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DIO1 | NM_000792.7 | c.388A>C | p.Met130Leu | missense_variant | 2/4 | ENST00000361921.8 | |
LOC124904180 | XR_007066095.1 | n.288+1695T>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DIO1 | ENST00000361921.8 | c.388A>C | p.Met130Leu | missense_variant | 2/4 | 1 | NM_000792.7 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000482 AC: 12AN: 249138Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135158
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GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461580Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727050
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74476
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ClinVar
Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 27, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D
PROVEAN
Benign
N;N;N;.;.;N;N
REVEL
Benign
Sift
Benign
T;T;T;.;.;T;T
Sift4G
Benign
T;T;T;T;T;T;T
Polyphen
0.0, 0.0020
.;B;B;.;.;B;.
Vest4
0.24, 0.23, 0.20
MutPred
0.69
.;Loss of methylation at K132 (P = 0.1261);Loss of methylation at K132 (P = 0.1261);.;.;.;.;
MVP
MPC
0.15
ClinPred
T
GERP RS
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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