20-50891465-T-TC

Position:

• chr20-50891465-T-TC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001282531.3(ADNP):​c.3248_3249insG​(p.Val1084SerfsTer3) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADNP NM_001282531.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.77

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 Uncertain_significance. Variant got 4 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. Fraction of 0.0184 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADNP	NM_001282531.3	c.3248_3249insG	p.Val1084SerfsTer3	frameshift_variant	6/6	ENST00000621696.5	NP_001269460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADNP	ENST00000621696.5	c.3248_3249insG	p.Val1084SerfsTer3	frameshift_variant	6/6	5	NM_001282531.3	ENSP00000483881	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 21, 2018

The c.3248dupG variant in the ADNP gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.3248dupG variant causes a frameshift starting with codon Valine 1084, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Val1084SerfsX3. This variant is predicted to cause loss of normal protein function through protein truncation. The c.3248dupG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.3248dupG as a variant of uncertain significance. -

ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

GenomeConnect - Simons Searchlight

Oct 01, 2018

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-10-01 and interpreted as Variant of Uncertain Significance. Variant was initially reported on 2018-06-08 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. -

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: rs1555809374; hg19: chr20-49508002;