chr20-50892214-CTTTA-C

Variant names:

• chr20-50892214-CTTTA-C
• rs587777523
• NM_001282531.3:c.2496_2499delTAAA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1_Strong PS3 PM2 PP5_Very_Strong

The NM_001282531.3(ADNP):​c.2496_2499delTAAA​(p.Asn832LysfsTer81) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000847584: Functional analysis was performed using immunolabeling of the well-established heterochromatin marker HP1&alpha" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADNP NM_001282531.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• Conservation: PhyloP100: 5.85
• Publications: 10 publications found

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]

ADNP Gene-Disease associations (from GenCC):

• ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 18 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000847584: Functional analysis was performed using immunolabeling of the well-established heterochromatin marker HP1α to verify co-localization of ADNP with heterochromatin. While the p.N832Kfs*81 alteration co-localized with HP1, researchers noted that specific enrichment at pericentromeric heterochromatin seemed partially lost (Cappuyns, 2018).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-50892214-CTTTA-C is Pathogenic according to our data. Variant chr20-50892214-CTTTA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 139632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282531.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADNP	NM_001282531.3	MANE Select	c.2496_2499delTAAA	p.Asn832LysfsTer81	frameshift	Exon 6 of 6	NP_001269460.1	Q9H2P0
	ADNP	NM_001439000.1		c.2712_2715delTAAA	p.Asn904LysfsTer81	frameshift	Exon 6 of 6	NP_001425929.1
	ADNP	NM_001282532.2		c.2496_2499delTAAA	p.Asn832LysfsTer81	frameshift	Exon 4 of 4	NP_001269461.1	Q9H2P0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADNP	ENST00000621696.5	TSL:5 MANE Select	c.2496_2499delTAAA	p.Asn832LysfsTer81	frameshift	Exon 6 of 6	ENSP00000483881.1	Q9H2P0
	ADNP	ENST00000349014.8	TSL:1	c.2496_2499delTAAA	p.Asn832LysfsTer81	frameshift	Exon 4 of 4	ENSP00000342905.3	Q9H2P0
	ADNP	ENST00000371602.9	TSL:1	c.2496_2499delTAAA	p.Asn832LysfsTer81	frameshift	Exon 3 of 3	ENSP00000360662.2	Q9H2P0

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder (13)
6	-	-	not provided (6)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777523; hg19: chr20-49508751;