3-123291354-A-T

Variant names:

• chr3-123291354-A-T
• rs864309484
• NM_183357.3:c.3086T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_183357.3(ADCY5):​c.3086T>A​(p.Met1029Lys) 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 (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADCY5 NM_183357.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.56

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ADCY5 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 45 curated benign missense variants. Gene score misZ: 3.4043 (above the threshold of 3.09). Trascript score misZ: 4.4657 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.863
• PP5: Variant 3-123291354-A-T is Pathogenic according to our data. Variant chr3-123291354-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 162092.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCY5	NM_183357.3	c.3086T>A	p.Met1029Lys	missense_variant	Exon 18 of 21	ENST00000462833.6	NP_899200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADCY5	ENST00000462833.6	c.3086T>A	p.Met1029Lys	missense_variant	Exon 18 of 21	1	NM_183357.3	ENSP00000419361.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 14, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.4	M;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.55	P;P;.
Vest4		0.93
MutPred		0.47		Loss of catalytic residue at M1029 (P = 3e-04);.;.;
MVP		0.96
MPC		2.0
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.95
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs864309484; hg19: chr3-123010201;