rs864309483

Positions:

• chr3-123352464-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000462833.6(ADCY5):​c.1252C>T​(p.Arg418Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R418Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADCY5 ENST00000462833.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 4.40

Genes affected

ADCY5 (HGNC:236): (adenylate cyclase 5) This gene encodes a member of the membrane-bound adenylyl cyclase enzymes. Adenylyl cyclases mediate G protein-coupled receptor signaling through the synthesis of the second messenger cAMP. Activity of the encoded protein is stimulated by the Gs alpha subunit of G protein-coupled receptors and is inhibited by protein kinase A, calcium and Gi alpha subunits. Single nucleotide polymorphisms in this gene may be associated with low birth weight and type 2 diabetes. Alternatively spliced transcript variants that encode different isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-123352463-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 218354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ADCY5. . Gene score misZ 3.4043 (greater than the threshold 3.09). Trascript score misZ 4.4657 (greater than threshold 3.09). GenCC has associacion of gene with dyskinesia with orofacial involvement, autosomal dominant, neurodevelopmental disorder with hyperkinetic movements and dyskinesia, choreatic disease, familial dyskinesia and facial myokymia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879
• PP5: Variant 3-123352464-G-A is Pathogenic according to our data. Variant chr3-123352464-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 162090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123352464-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADCY5	NM_183357.3	c.1252C>T	p.Arg418Trp	missense_variant	2/21	ENST00000462833.6	NP_899200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADCY5	ENST00000462833.6	c.1252C>T	p.Arg418Trp	missense_variant	2/21	1	NM_183357.3	ENSP00000419361	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dyskinesia with orofacial involvement, autosomal dominant Pathogenic:7 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with autosomal recessive dyskinesia with orofacial involvement (MIM#619647) and autosomal dominant dyskinesia with orofacial involvement (MIM#606703), respectively. Loss of function is the likely mechanism of neurodevelopmental disorder with hyperkinetic movements and dyskinesia (PMID: 28971144, PMID: 30975617). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0254 - This variant is confirmed mosaic. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated AC_N domain (NCBI conserved domain). (I) 0703 - Other variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. These alternative changes (p.(Arg418Gln), p.(Arg418Gly), p.Arg418Thr)) have been previously reported (ClinVar, PMID: 28511835, PMID: 28442302). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic and de novo in individuals with childhood onset involuntary paroxysmal choreiform and dystonic movements. In one individual, the variant was mosaic (ClinVar, PMID: 24700542, PMID: 28511835, PMID: 32713175). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function, demonstrating increased adenyl cyclase activity compared to wildtype controls (PMID: 24700542). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 25, 2018	- -
Pathogenic, criteria provided, single submitter	research	Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute	Dec 15, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 13, 2019	- -

not provided Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 418 of the ADCY5 protein (p.Arg418Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ADCY5-related dyskinesia (PMID: 24700542, 26085604). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 162090). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ADCY5 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ADCY5 function (PMID: 24700542). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2022	Published functional studies demonstrate a damaging effect; specifically, the R418W variant revealed significant increase in intracellular cAMP and adenylyl cyclase activity, as compared to wild type, consistent with a gain-of-function effect (Chen et al., 2014; Doyle et al., 2019).; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24700542, 25790160, 26537056, 30772269, 31422281, 29996192, 31628766, 32713175, 26085604, 27052971, 26686870, 29473048, 28511835, 28849312, 30345538, 33426171, 33827957, 33098801) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D;T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.8	H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.7	D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.92
MutPred		0.64		Loss of disorder (P = 2e-04);.;.;
MVP		0.97
MPC		2.1
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.63
gMVP		0.86

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: rs864309483; hg19: chr3-123071311; COSMIC: COSV100567383;