chr3-123352463-C-T

Position:

• chr3-123352463-C-T

Variant summary

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

The NM_183357.3(ADCY5):​c.1253G>A​(p.Arg418Gln) variant causes a missense change involving the alteration of a conserved nucleotide. 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. R418W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADCY5 NM_183357.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 7.73

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 chr3-123352464-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.
• 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, 0.868
• PP5: Variant 3-123352463-C-T is Pathogenic according to our data. 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. Variant chr3-123352463-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY5	NM_183357.3	c.1253G>A	p.Arg418Gln	missense_variant	2/21	ENST00000462833.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY5	ENST00000462833.6	c.1253G>A	p.Arg418Gln	missense_variant	2/21	1	NM_183357.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461298 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 15, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg418 amino acid residue in ADCY5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24700542, 26085604). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ADCY5 function (PMID: 30772269). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADCY5 protein function. ClinVar contains an entry for this variant (Variation ID: 218354). This missense change has been observed in individual(s) with ADCY5-related conditions (PMID: 26537056, 28511835). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 418 of the ADCY5 protein (p.Arg418Gln). -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28442302, 27933653, 30772269, 31970214, 26686870, 28229249, 27931826, 29086067, 28511835, 29473048, 27061943, 30172639, 31737037, 35872528, 35002175, 26537056) -
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	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2021	- -

Dyskinesia with orofacial involvement, autosomal dominant Pathogenic:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 30, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 10, 2021	- -

Neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

-

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Nov 21, 2022

ACMG categories: PS1,PS4,PP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D;T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.9	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.018	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.88
MutPred		0.60		Loss of catalytic residue at R418 (P = 0.0034);.;.;
MVP		0.93
MPC		1.9
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.64
gMVP		0.82

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: rs864309515; hg19: chr3-123071310;