rs1135401808

Variant names:

• chr20-50892557-G-GT
• rs1135401808
• NM_001282531.3:c.2156dupA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001282531.3(ADNP):​c.2156dupA​(p.Tyr719fs) variant causes a frameshift, stop gained change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADNP NM_001282531.3 frameshift, stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 3.69

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 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 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-50892557-G-GT is Pathogenic according to our data. Variant chr20-50892557-G-GT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190278.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.2156dupA	p.Tyr719fs	frameshift_variant, stop_gained	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.2156dupA	p.Tyr719fs	frameshift_variant, stop_gained	Exon 6 of 6	5	NM_001282531.3	ENSP00000483881.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

Jul 26, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (Ivashko-Pachima Y et al., 2019); Not observed in large population cohorts (gnomAD); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 384 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 31332282, 28221363, 24531329, 29724491, 29911927, 28135719, 30679581, 31035039, 28708303, 31981491, 33673501, 31664177, 23160955, 31526516, 32758449, 32410215, 33004838, 24077912, 31785789) -

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Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect ADNP protein function (PMID: 29911927). This sequence change results in a premature translational stop signal in the ADNP gene (p.Tyr719*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 384 amino acids of the ADNP protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Helsmoortel-van der Aa syndrome (PMID: 28221363, 28708303). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 190278). -

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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

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ADNP: PS2:Very Strong, PVS1:Strong, PM2, PS4:Moderate, PS3:Supporting -

ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder Pathogenic:5

Mar 12, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 06, 2017

Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intellectual disability, severe; antenatal cerebral ventriculomegaly; aggressive behaviour; small stature; probable neuropathy; stereotypies; dental disease; dysmorphism -

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2015

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Dec 13, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2156dupA pathogenic mutation, located in coding exon 3 of the ADNP gene, results from a duplication of A at nucleotide position 2156. This changes the amino acid from a tyrosine to a stop codon within coding exon 3 (p.Y719*). This mutation has been detected as de novo occurrences in multiple individuals in the literature with autism, various types of developmental delays, intellectual disability, and dysmorphic features (Gozes I et al. Transl Psychiatry, 2017 02;7:e1043; Gozes I et al. Front Endocrinol (Lausanne), 2017 May;8:107; Van Dijck A et al. Biol. Psychiatry, 2018 Mar; Helsmoortel C et al. Nat. Genet., 2014 Apr;46:380-4; Pescosolido MF et al. J. Med. Genet., 2014 Sep;51:587-9; O'Roak BJ et al. Science, 2012 Dec;338:1619-22; Chérot E et al. Clin. Genet., 2018 Mar;93:567-576).This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Neurodevelopmental disorder Pathogenic:1

Dec 17, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability Pathogenic:1

Dec 01, 2017

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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: rs1135401808; hg19: chr20-49509094;