20-50892557-G-T

Variant names:

• chr20-50892557-G-T
• rs587777526
• NM_001282531.3:c.2157C>A

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.2157C>A​(p.Tyr719*) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADNP NM_001282531.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: -1.13

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-T is Pathogenic according to our data. Variant chr20-50892557-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 280623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-50892557-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADNP	NM_001282531.3	c.2157C>A	p.Tyr719*	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.2157C>A	p.Tyr719*	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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder Pathogenic:3

Mar 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Stop-gained (nonsense): 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%. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 28221363). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 29724491). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 26, 2016

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 2016-01-26 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. -

Feb 24, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ADNP: PS2, PVS1:Strong, PM2, PS4:Moderate -

Jan 02, 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 384 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: 28221363, 25057125, 24531329, 28579975, 29724491, 29780943, 30107084, 29475819, 31029150, 29911927, 32758449, 31526516, 33004838) -

Inborn genetic diseases Pathogenic:1

Oct 29, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2157C>A (p.Y719*) alteration, located in exon 5 (coding exon 3) of the ADNP gene, consists of a C to A substitution at nucleotide position 2157. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 719. This alteration occurs at the 3' terminus of the ADNP gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 34.8% of the protein. Premature stop codons are typically deleterious in nature. The impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This is a recurrent variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with ADNP-related neurodevelopmental disorder (Gale, 2018; Van Dijck, 2019). Based on the available evidence, this alteration is classified as pathogenic. -

ADNP-related disorder Pathogenic:1

Sep 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ADNP c.2157C>A variant is predicted to result in premature protein termination (p.Tyr719*). This variant is one of the recurrent de novo pathogenic variants reported in individuals with Helsmoortel-van der Aa syndrome (see for example Gozes. et al. 2017. PubMed ID: 28579975; Van Dijck et al. 2016. PMID: 27054228; Van Dijck et al. 2018. PubMed ID: 29724491; Breen et al. 2020. PubMed ID: 32758449). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in ADNP are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Benign	0.84
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.25	N
Vest4		0.93
GERP RS		-12

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: rs587777526; hg19: chr20-49509094;