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

Genomes: not found (cov: 33)

Consequence

ADNP
NM_001282531.3 stop_gained

Scores

2
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21O:1

Conservation

PhyloP100: 1.36
Variant links:
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]

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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. There are 8 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 20-50892526-G-A is Pathogenic according to our data. Variant chr20-50892526-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 279598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-50892526-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADNPNM_001282531.3 linkc.2188C>T p.Arg730* stop_gained Exon 6 of 6 ENST00000621696.5 NP_001269460.1 Q9H2P0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADNPENST00000621696.5 linkc.2188C>T p.Arg730* stop_gained Exon 6 of 6 5 NM_001282531.3 ENSP00000483881.1 Q9H2P0

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:21Other: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
Feb 21, 2019
Undiagnosed Diseases Network, NIH
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

Common pathogenic variant -

Oct 25, 2022
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

_x000D_This variant was identified as de novo (maternity and paternity confirmed). Criteria applied: PVS1, PS2_VSTR, PS4, PM2_SUP -

Sep 30, 2016
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 03, 2024
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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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Molecular Genetics Lab, CHRU Brest
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Juno Genomics, Hangzhou Juno Genomics, Inc
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2_Supporting+PVS1_Strong+PS4_Moderate+PS2_Moderate+PP4 -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 14, 2019
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jan 06, 2020
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

ACMG codes: PVS1, PS2, PS4M, PM2, PP5 -

Jun 01, 2016
Center of Genomic medicine, Geneva, University Hospital of Geneva
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:9
Jun 17, 2021
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 27, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 01, 2020
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 11, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Jul 08, 2024
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.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. -

Sep 14, 2022
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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Oct 10, 2021
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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Inborn genetic diseases Pathogenic:1
Aug 03, 2017
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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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
Mar 21, 2016
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.59
D
BayesDel_noAF
Pathogenic
0.46
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Uncertain
0.92
D
Vest4
0.92
GERP RS
2.8

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs886041116; hg19: chr20-49509063; COSMIC: COSV100823721; COSMIC: COSV100823721; API