rs886041116

chr20-50892526-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001282531.3(ADNP):c.2188C>T(p.Arg730Ter) 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: 1.36

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 32 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/exons	MANE	UniProt
ADNP	NM_001282531.3	c.2188C>T	p.Arg730Ter	stop_gained	6/6	ENST00000621696.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADNP	ENST00000621696.5	c.2188C>T	p.Arg730Ter	stop_gained	6/6	5	NM_001282531.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Sep 30, 2016	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jan 06, 2020	ACMG codes: PVS1, PS2, PS4M, PM2, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Jun 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Feb 21, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Lab, CHRU Brest	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 25, 2022	_x000D_This variant was identified as de novo (maternity and paternity confirmed). Criteria applied: PVS1, PS2_VSTR, PS4, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	May 14, 2019	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. -
not provided, no classification provided	literature only	GeneReviews	-	Common pathogenic variant -

not provided Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 14, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2023	For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this premature translational stop signal affects ADNP function (PMID: 29911927). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 279598). This premature translational stop signal has been observed in individual(s) with Helsmoortel-van der Aa syndrome (PMID: 29911927). This variant is not present in population databases (gnomAD no frequency). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2022	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) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2017

- -

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

Likely pathogenic, no assertion criteria provided

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Mar 21, 2016

- -

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
MutationTaster	Benign	1.0	D;D;D;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

Other links and lift over

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