rs527236031
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_015937.6(PIGT):c.1342C>T(p.Arg448Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,058 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 Likely pathogenic (★★).
Frequency
Consequence
NM_015937.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152186Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250168Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135258
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461872Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11AN XY: 727240
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152186Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74344
ClinVar
Submissions by phenotype
Multiple congenital anomalies-hypotonia-seizures syndrome 3 Pathogenic:5
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The missense variant c.1342C>T (p.Arg448Trp) in PIGT gene has been observed to segregate with multiple congenital anomalies-hypotonia-seizures syndrome in a family(Nakashima M et.al.,2014). This variant has been reported to the ClinVar database as Likely Pathogenic. The p.Arg448Trp variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.001776% is reported in gnomAD. The amino acid Arg at position 448 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg448Trp in PIGT is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -
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This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 448 of the PIGT protein (p.Arg448Trp). This variant is present in population databases (rs527236031, gnomAD 0.01%). This missense change has been observed in individual(s) with multiple congenital anomalies-hypotonia-seizures syndrome (PMID: 24906948, 25943031). 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. ClinVar contains an entry for this variant (Variation ID: 143194). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PIGT protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Same nucleotide change resulting in same amino acid change has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 24906948, 25943031, 34046058, 3billion dataset, PM3_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.00001776, PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.809, 3Cnet: 0.857, PP3). Patient's phenotype is considered compatible with Multiple congenital anomalies-hypotonia-seizures syndrome 3 (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at