rs142247083

chr20-50891435-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001282531.3(ADNP):c.3279C>T(p.Ala1093=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,610,974 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00091 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: ADNP NM_001282531.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.83

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 20-50891435-G-A is Benign according to our data. Variant chr20-50891435-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 434090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.83 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000907 (138/152192) while in subpopulation NFE AF= 0.0015 (102/68040). AF 95% confidence interval is 0.00126. There are 1 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 138 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADNP	NM_001282531.3	c.3279C>T	p.Ala1093=	synonymous_variant	6/6	ENST00000621696.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADNP	ENST00000621696.5	c.3279C>T	p.Ala1093=	synonymous_variant	6/6	5	NM_001282531.3	P1

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152192 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000899 AC: 223 AN: 248066 Hom.: 0 AF XY: 0.000835 AC XY: 112 AN XY: 134124

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.000552

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.000147

Gnomad NFE exome AF: 0.00158

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00189 AC: 2753 AN: 1458782 Hom.: 6 Cov.: 35 AF XY: 0.00181 AC XY: 1313 AN XY: 725706

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000516

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000268

Gnomad4 FIN exome AF: 0.000212

Gnomad4 NFE exome AF: 0.00235

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000907 AC: 138 AN: 152192 Hom.: 1 Cov.: 33 AF XY: 0.000659 AC XY: 49 AN XY: 74350

Gnomad4 AFR AF: 0.000627

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00150

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.00107

EpiCase AF: 0.00131

EpiControl AF: 0.00184

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 31, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 01, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

ADNP-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.38
Dann	Benign	0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs142247083; hg19: chr20-49507972;