chr20-50892526-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001282531.3(ADNP):c.2188C>T(p.Arg730*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001282531.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 35
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder Pathogenic:10Other:1
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Common pathogenic variant -
_x000D_This variant was identified as de novo (maternity and paternity confirmed). Criteria applied: PVS1, PS2_VSTR, PS4, PM2_SUP -
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This sequence variant is a single nucleotide substitution (C>T) at position 2188 of the coding sequence of the ADNP gene which changes the Arg730 codon to an early termination codon. Although this variant occurs in the last of 5 exons in this gene, it is predicted to generate a non-functional allele through the expression of a truncated protein (PMID: 29724491). This is a previously reported variant (ClinVar 279598) that has been observed de novo in individuals affected by autism spectrum disorder, intellectual disability, developmental disability, and Helsmoortel–Van der Aa syndrome (PMID: 38254177, 29724491, 38204290, 29475819, 35322241, 27031564, 35813072, 35920977, 38282129, 31029150, 35982159, 28675391, 28407407). This variant is absent from the gnomAD v4.0.0 population database (0/~1,461,000 alleles). Haploinsufficiency in ADNP is a known mechanism of disease. Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PS2, PVS1 -
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PM2_Supporting+PVS1_Strong+PS4_Moderate+PS2_Moderate+PP4 -
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This nonsense variant is found in exon 5 of 5 and is predicted to result in loss of normal protein function. This variant has been reported as Pathogenic by multiple clinical laboratories in the ClinVar database (Variation ID: 279598). Additionally, this variant has been previously reported in the literature as a de novo heterozygous change in patients with Helsmoortel-van der Aa Syndrome (PMID: 27031564, 29286531, 29724491). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Based on the available evidence, the c.2188C>T (p.Arg730Ter) variant is classified as Pathogenic. -
ACMG codes: PVS1, PS2, PS4M, PM2, PP5 -
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not provided Pathogenic:9
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Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 373 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29475819, 27031564, 29911927, 31029150, 29286531, 29724491, 31664177, 24531329, 28221363, 32661233, 33329371, 32758449, 31785789, 34930662, 33004838) -
This sequence change creates a premature translational stop signal (p.Arg730*) in the ADNP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 373 amino acid(s) of the ADNP protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Helsmoortel-van der Aa syndrome (PMID: 29911927). ClinVar contains an entry for this variant (Variation ID: 279598). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ADNP function (PMID: 29911927). This variant disrupts a region of the ADNP protein in which other variant(s) (p.Met1088Serfs*5) have been determined to be pathogenic (PMID: 28135719). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
The ADNP c.2188C>T (p.Arg730Ter) nonsense variant results in the substitution of arginine at amino acid position 730 with a stop codon. This variant occurs in the last exon of the gene and may escape nonsense-mediated mRNA decay. Across a selection of the available literature, the c.2188C>T variant, which is described as one of the most common pathogenic ADNP variants, has been reported in a heterozygous state in at least seven patients with ADNP-related neurodevelopmental disorder (PMID: 27031564; PMID: 28221363; PMID: 29475819; PMID: 29724491). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. In-vitro cell culture studies showed that although the variant protein is able to translocate inside the nucleus and co-localize with its binding partner, it does so less efficiently in the pericentromeric heterochromatin region when compared to wild-type protein (PMID: 29911927). Based on the available evidence, the c.2188C>T (p.Arg730Ter) variant is classified as pathogenic for ADNP-related neurodevelopmental disorder. -
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Inborn genetic diseases Pathogenic:1
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Aggressive behavior;C0020676:Hypothyroidism;C0036572:Seizure;C0038273:Stereotypic movement disorder;C0175754:Corpus callosum, agenesis of;C0262444:Abnormality of the dentition;C0557874:Global developmental delay;C5539399:Decreased response to growth hormone stimulation test Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at