chr20-50891666-C-CT

Variant names:

• chr20-50891666-C-CT
• rs761350619
• NM_001282531.3:c.3047dupA

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PVS1_Strong PP5 BS2

The NM_001282531.3(ADNP):​c.3047dupA​(p.Ala1017GlyfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,540 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: ADNP NM_001282531.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 0.157

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

Our verdict: Uncertain_significance. The variant received 1 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 4 pathogenic variants in the truncated region.
• PP5: Variant 20-50891666-C-CT is Pathogenic according to our data. Variant chr20-50891666-C-CT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2501307.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADNP	NM_001282531.3	c.3047dupA	p.Ala1017GlyfsTer6	frameshift_variant	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.3047dupA	p.Ala1017GlyfsTer6	frameshift_variant	Exon 6 of 6	5	NM_001282531.3	ENSP00000483881.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151968 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248546 AF XY: 0.0000298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461572 Hom.: 0 Cov.: 35 AF XY: 0.0000206 AC XY: 15 AN XY: 727082

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111884

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151968 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74220

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.0000656 AC: 1 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder Pathogenic:2

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed frameshift variant c.3047dup(p.Ala1017GlyfsTer6) in the ADNP gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.002% in the gnomAD Exomes. This variant causes a frameshift starting with codon Alanine 1017, changes this amino acid to Glycine residue, and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Ala1017GlyfsTer6. Though this variant is present in the last exon, there are three heterozygous variants reported beyond this position in the ClinVar database. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (Van Dijck A, et al., 2019). For these reasons, this variant has been classified as Likely Pathogenic. -

Sep 11, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ADNP c.3047dupA (p.Ala1017GlyfsX6) results in a premature termination codon in the last exon, therefore it is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein (removing the C-terminal part of the 1102 amino acid long protein). Truncations downstream from this position have been reported in affected individuals (HGMD). The variant allele was found at a frequency of 1.6e-05 in 248546 control chromosomes in the gnomAD database, exomes dataset (i.e. 4 / 248546 alleles, however these four samples didn't pass the quality filters, therefore the occurrence data might not be reliable). The variant, c.3047dupA, has been reported in the literature in individuals affected with ADNP-Related Multiple Congenital Anomalies-Intellectual Disability-Autism Spectrum Disorder (e.g. Guo_2018, VanDijck_2018, Wang_2020), and in multiple cases the variant was noted to be inherited from an apparently unaffected parent, or from a parent with milder phenotype. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30564305, 29724491, 33004838). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1 Uncertain:1

Aug 18, 2023

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 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. ClinVar contains an entry for this variant (Variation ID: 2501307). This premature translational stop signal has been observed in individual(s) with clinical features of Helsmoortel-Van der Aa syndrome (PMID: 29724491, 33004838). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Ala1017Glyfs*6) in the ADNP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 86 amino acid(s) of the ADNP protein. -

Jun 18, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in large scale studies of individuals with autism or unspecified developmental disorders in the published literature (PMID: 29724491, 33004838); Frameshift variant predicted to result in protein truncation as the last 86 amino acids are lost and replaced with 5 incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 27308845, 33004838, 29724491, 37506195, 30564305, 28135719) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16
Mutation Taster		=0/200	disease causing

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: rs761350619; hg19: chr20-49508203; COSMIC: COSV62424622; COSMIC: COSV62424622;