chr20-50902017-C-G

Variant names:

• chr20-50902017-C-G
• rs1555812161
• NM_001282531.3:c.201G>C

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 1 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, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious 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 VariationId is 521542.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADNP	NM_001282531.3	c.201G>C	p.Gln67His	missense_variant, splice_region_variant	Exon 5 of 6	ENST00000621696.5	NP_001269460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADNP	ENST00000621696.5	c.201G>C	p.Gln67His	missense_variant, splice_region_variant	Exon 5 of 6	5	NM_001282531.3	ENSP00000483881.1

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

Oct 04, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 12, 2018

GenomeConnect - Simons Searchlight

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

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
LIST_S2	Uncertain	0.92	.;D;T;.;.;.;.
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;.
PhyloP100		5.5
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
Mutation Taster		=33/67	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555812161; hg19: chr20-49518554;