rs587777523

Variant names:

• chr20-50892214-CTTTA-C
• rs587777523
• NM_001282531.3:c.2496_2499delTAAA

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001282531.3(ADNP):​c.2496_2499delTAAA​(p.Asn832LysfsTer81) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADNP NM_001282531.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• Conservation: PhyloP100: 5.85
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

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

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 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. There are 18 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 VariationId is 139632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADNP	NM_001282531.3	c.2496_2499delTAAA	p.Asn832LysfsTer81	frameshift_variant	Exon 6 of 6	ENST00000621696.5	NP_001269460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADNP	ENST00000621696.5	c.2496_2499delTAAA	p.Asn832LysfsTer81	frameshift_variant	Exon 6 of 6	5	NM_001282531.3	ENSP00000483881.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder Pathogenic:12 Other:1

Jul 02, 2018

GenomeConnect - Simons Searchlight

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

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. -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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 -

Jan 25, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 24, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 20, 2024

Institute of Human Genetics, Cologne University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 01, 2025

Center of Human Genetics, Hôpital Erasme

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jul 21, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as de novo (maternity and paternity confirmed). -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1_Strong+PS2_Moderate+PS4 -

not provided Pathogenic:6

Apr 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 24, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Dec 14, 2016

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 21, 2020

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 26, 2018

Molecular Genetics laboratory, Necker Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Inborn genetic diseases Pathogenic:1

Jun 14, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs587777523; hg19: chr20-49508751;