Variant 20-50892214-CTTTA-C details in Genebe, Genetics Data Aggregator

Genes affected

ADNP (HGNC:15766): (activity dependent neuroprotector homeobox) Vasoactive intestinal peptide is a neuroprotective factor that has a stimulatory effect on the growth of some tumor cells and an inhibitory effect on others. This gene encodes a protein that is upregulated by vasoactive intestinal peptide and may be involved in its stimulatory effect on certain tumor cells. The encoded protein contains one homeobox and nine zinc finger domains, suggesting that it functions as a transcription factor. This gene is also upregulated in normal proliferative tissues. Finally, the encoded protein may increase the viability of certain cell types through modulation of p53 activity. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jul 2008]

ADNP links:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.246 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-50892214-CTTTA-C is Pathogenic according to our data. Variant chr20-50892214-CTTTA-C is described in ClinVar as [Pathogenic]. Clinvar id is 139632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-50892214-CTTTA-C is described in Lovd as [Pathogenic]. Variant chr20-50892214-CTTTA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADNP	NM_001282531.3 linkuse as main transcript	c.2496_2499del	p.Asn832LysfsTer81	frameshift_variant	6/6	ENST00000621696.5	NP_001269460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADNP	ENST00000621696.5 linkuse as main transcript	c.2496_2499del	p.Asn832LysfsTer81	frameshift_variant	6/6	5	NM_001282531.3	ENSP00000483881	P1

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder

Pathogenic:10Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This mutation has been described in the literature as disease-causing and has been identified once in our laboratory as a de novo mutation in a 17-year-old male with intellectual disability, dysmorphic features, short stature, microcephaly, and obesity -
not provided, no classification provided	literature only	GeneReviews	-	All other pathogenic variants are heterozygous frameshift or nonsense variants in the 3-prime end of 5th (last) exon of ADNP and predict a premature termination -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 25, 2024	Variant summary: ADNP c.2496_2499delTAAA (p.Asn832LysfsX81) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. The variant was absent in 251334 control chromosomes (gnomAD). c.2496_2499delTAAA has been reported in the literature as a de denovo occurrence in multiple individuals affected with Helsmoortel-Van Der Aa Syndrome and autism spectrum disorder with developmental delay (examples: Helsmoortel_2014, Gozes_2017, Krgovic_2022, Maron_2023). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 37432431, 24531329, 35813072, 28221363). ClinVar contains an entry for this variant (Variation ID: 139632). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Cologne University	Sep 20, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 21, 2021	This variant was identified as de novo (maternity and paternity confirmed). -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Helsmoortel-van der Aa syndrome (MIM#615873) (PMID: 29911927). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten other individuals with ADNP-related disorder and consistently classified as pathogenic by diagnostic laboratories in ClinVar (DECIPHER; PMID: 32275126, 29724491, 24531329). (SP) 1102 - Strong phenotype match for this individual. (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 24, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000139632 / PMID: 24531329). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	Jul 02, 2018	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-07-02 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. -

not provided

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	Dec 14, 2016	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics laboratory, Necker Hospital	Apr 26, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 21, 2020	ADNP frameshift variants are known to be pathogenic and multiple frameshift variants in this region have been reported in patients with Helsmoortel-van der Aa syndrome (PMID: 29724491, 24531329). This variant has been reported to occur de novo in multiple individuals with clinical features associated with this gene (PMID:24531329, 28221363, 32275126). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2022	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 271 amino acids are lost and replaced with 80 incorrect amino acids (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26845106, 29724491, 24531329, 24866042, 25533962, 28191890, 30107084, 28221363, 29911927, 28135719, 32275126, 32758449, 31526516, 32719394, 31785789, 33004838, 25326635) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 05, 2023	This sequence change creates a premature translational stop signal (p.Asn832Lysfs*81) in the ADNP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 271 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 individuals with clinical features of Helsmoortel-Van der Aa syndrome (PMID: 24531329, 28221363, 32275126; Invitae). ClinVar contains an entry for this variant (Variation ID: 139632). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2018	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2022

The c.2496_2499delTAAA (p.N832Kfs*81) alteration, located in exon 5 (coding exon 3) of the ADNP gene, consists of a deletion of 4 nucleotides from position 2496 to 2499, causing a translational frameshift with a predicted alternate stop codon after 81 amino acids. This alteration occurs at the 3' terminus of the ADNP gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 24.5% of the protein. Premature stop codons are typically deleterious in nature and a significant portion of the protein is affected. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was detected as a de novo occurrence in multiple individuals with neurodevelopmental disorders (Helsmoortel, 2014; Gozes, 2017; Van Dijck, 2019; Shillington, 2020). Functional analysis was performed using immunolabeling of the well-established heterochromatin marker HP1α to verify co-localization of ADNP with heterochromatin. While the p.N832Kfs*81 alteration co-localized with HP1, researchers noted that specific enrichment at pericentromeric heterochromatin seemed partially lost (Cappuyns, 2018). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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Splicing

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SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

20-50892214-CTTTA-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation