chr20-50894171-CCTAA-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001282531.3(ADNP):c.539_542delTTAG(p.Val180GlyfsTer17) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001282531.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder Pathogenic:6
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The ADNP c.539_542delTTAG (p.Val180GlyfsTer17) variant is a frameshift variant that has been identified in one study, in which it is found in a de novo heterozygous state in one individual with ADNP-related neurodevelopmental disorder (Bend et al. 2019). The p.Val180GlyfsTer17 variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the potential impact of truncating variants in this gene, its rarity, its identification in a patient in the literature, and application of the ACMG criteria, the p.Val180GlyfsTer17 variant is classified as pathogenic for ADNP-related neurodevelopmental disorder. -
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not provided Pathogenic:4
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Frameshift variant predicted to result in abnormal protein length as the last 923 amino acids are replaced with 16 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29724491, 31029150, 35904121, 33860439, 35982159, 31785789, 36474027, 32758449, 31526516, Aspromonte2023[pre-print], 36553633, 28221363) -
ADNP: PS2, PVS1:Strong, PM2, PS4:Moderate -
This sequence change creates a premature translational stop signal (p.Val180Glyfs*17) in the ADNP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 923 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 clinical features of Helsmoortel-Van der Aa syndrome (PMID: 28675391, 31029150). ClinVar contains an entry for this variant (Variation ID: 373314). This variant disrupts a region of the ADNP protein in which other variant(s) (p.Tyr719*) have been determined to be pathogenic (PMID: 28221363, 28708303, 29911927). 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. -
Inborn genetic diseases Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at