20-50892557-G-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001282531.3(ADNP):c.2157C>G(p.Tyr719*) 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 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
GnomAD4 exome Cov.: 35
GnomAD4 genome
ClinVar
Submissions by phenotype
ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder Pathogenic:8Other:1
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Pathogenic variant in exon 4; associated with later onset of walking and higher pain threshold than other ADNP pathogenic variants -
Based on the classification scheme VCGS_Germline_v1.1.0, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0204 - Variant is predicted to result in a truncated protein with more than 1/3 of the protein affected. (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0600 - Variant is located upstream of an annotated domain or motif (Homeodomain; NCBI, PDB). (N) 0701 - Comparable variants have very strong previous evidence for pathogenicity (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar, Deciphering Developmental Disorders Study, Helsmoortel, C. et al. (2014)). (P) 1102 - Strong phenotype match. (P) 1203 - Variant shown to be de novo in proband (parental status confirmed). (P) -
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The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). Predicted Consequence/Location: Missense variant Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 22131351, 23748425). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.78 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 11174330).The variant has been observed in at least two similarly affected unrelated individuals (PMID: 11174330, 20641121, 27532257, 29121657).The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (3billion dataset).The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 11174330). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
The ADNP c.2157C>G (p.Tyr719Ter) variant is a stop-gained variant that is predicted to result in a premature termination or absence of the protein. This variant is located in the last exon and may escape nonsense-mediated decay. Across a selection of literature, the p.Tyr719Ter variant has been reported in a de novo heterozygous state in at least eight probands with a phenotype consistent with ADNP-related neurodevelopmental disorder (Helsmoortel et al. 2014; Pescosolido et al. 2014; Gozes et al. 2017). Van Dijck et al. 2019) noted that individuals with the p.Tyr719Ter variant walk later and have a higher pain threshold than individuals with other pathogenic ADNP variants. This variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequencing coverage, which suggests the variant is rare. Based on the collective evidence, the p.Tyr719Ter variant is classified as pathogenic for ADNP-related neurodevelopmental disorder. -
not provided Pathogenic:2
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 384 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29724491, 25057125, 28407407, 28221363, 24531329, 29911927, 29475819, 31785789, 33004838, 32758449, 31526516) -
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 139635). This premature translational stop signal has been observed in individual(s) with Helsmoortel-van der Aa syndrome (PMID: 28221363, 28708303). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr719*) in the ADNP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 384 amino acid(s) of the ADNP protein. -
Inborn genetic diseases Pathogenic:1
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ADNP-related disorder Pathogenic:1
The ADNP c.2157C>G variant is predicted to result in premature protein termination (p.Tyr719*). This variant has been reported in patients with intellectual disability, autism and dysmorphic features, and in most cases it was reported to be de novo (see, for example, Helsmoortel et al. 2014. PubMed ID: 24531329; Takenouchi et al. 2017. PubMed ID: 28407407; Van Dijck et al. 2018. PubMed ID: 29724491). In vitro experimental studies indicate this variant affects protein function (Gozes et al. 2017. PubMed ID: 28221363; Cappuyns et al. 2018. PubMed ID: 29911927). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in ADNP are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at