8-132873226-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_003235.5(TG):c.638+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.0000198 in 1,613,916 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_003235.5 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TG | NM_003235.5 | c.638+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000220616.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TG | ENST00000220616.9 | c.638+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_003235.5 | P1 | |||
TG | ENST00000523901.1 | c.*489+5G>A | splice_donor_5th_base_variant, intron_variant, NMD_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250974Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135680
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461748Hom.: 1 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 727156
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74334
ClinVar
Submissions by phenotype
Iodotyrosyl coupling defect Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 28, 2016 | The TG c.638+5G>A variant is a splice region variant that has been reported in one study in which it was found in a homozygous state in two Turkish siblings with thyroid dyshormonogenesis (Li et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00003 in the Total population of the Exome Aggregation Consortium. Functional studies using RT-PCR revealed the c.638+5G>A variant resulted in a loss of exon 5. However, not all transcripts with the c.638+5G>A variant were mis-spliced, as demonstrated by faint banding consistent with wild type. The evidence for this variant is limited. The c.638+5G>A variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for thyroid dyshormonogenesis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | research | Pediatric Genetics Division, Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg | Sep 01, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at