rs1555812161

chr20-50902017-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_001282531.3(ADNP):c.201G>C(p.Gln67His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADNP NM_001282531.3 missense, splice_region
• Scores: Splicing: ADA: 0.9982
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.46

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 20-50902017-C-G is Pathogenic according to our data. Variant chr20-50902017-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521542.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADNP	NM_001282531.3	c.201G>C	p.Gln67His	missense_variant, splice_region_variant	5/6	ENST00000621696.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADNP	ENST00000621696.5	c.201G>C	p.Gln67His	missense_variant, splice_region_variant	5/6	5	NM_001282531.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2017

- -

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

Likely pathogenic, no assertion criteria provided

provider interpretation

GenomeConnect - Simons Searchlight

Jan 12, 2018

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-01-12 and interpreted as Likely Pathogenic. Variant was initially reported on 2017-03-15 by GTR ID of laboratory name 61756. The reporting laboratory might also submit to ClinVar. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	33
Dann	Uncertain	0.99
DEOGEN2	Benign	0.32	T;T;.;T;T;T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.016	D
MutationAssessor	Uncertain	2.3	M;M;.;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.5	N;.;.;N;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.069	T;.;.;T;T;T;T
Sift4G	Pathogenic	0.0	D;D;.;D;D;D;.
Polyphen		0.99	D;D;.;D;D;D;.
Vest4		0.63
MutPred		0.31		Gain of ubiquitination at K72 (P = 0.0985);Gain of ubiquitination at K72 (P = 0.0985);Gain of ubiquitination at K72 (P = 0.0985);Gain of ubiquitination at K72 (P = 0.0985);Gain of ubiquitination at K72 (P = 0.0985);Gain of ubiquitination at K72 (P = 0.0985);Gain of ubiquitination at K72 (P = 0.0985);
MVP		0.68
ClinPred		0.87	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.24		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555812161; hg19: chr20-49518554;