rs1057518345

chr20-50894171-CCTAA-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001282531.3(ADNP):c.539_542del(p.Val180GlyfsTer17) variant causes a frameshift change involving the alteration of a conserved nucleotide. 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:11
• Conservation: PhyloP100: 8.93

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 16 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 83 pathogenic variants in the truncated region.
• PP5: Variant 20-50894171-CCTAA-C is Pathogenic according to our data. Variant chr20-50894171-CCTAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 373314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-50894171-CCTAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADNP	NM_001282531.3	c.539_542del	p.Val180GlyfsTer17	frameshift_variant	6/6	ENST00000621696.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADNP	ENST00000621696.5	c.539_542del	p.Val180GlyfsTer17	frameshift_variant	6/6	5	NM_001282531.3	P1

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, University of Torino	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	May 28, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Feb 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Aug 02, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 27, 2020	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. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2020	Reported previously in individuals with features suggestive of Helsmoortel-van der Aa syndrome, but limited information was provided on these individuals (Gozes et al., 2017; van Dijck et al., 2019; Bend et al., 2019); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 923 amino acids are lost and replaced with 16 incorrect amino acids; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28221363, 29724491, 31029150, 32758449) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ADNP: PS2, PVS1:Strong, PM2, PS4:Moderate -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2015

- -

Computational scores

Source: dbNSFP v4.3

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: rs1057518345; hg19: chr20-49510708;