3-123284718-G-A

Variant names:

• chr3-123284718-G-A
• rs1553715806
• NM_183357.3:c.3676C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_183357.3(ADCY5):​c.3676C>T​(p.Gln1226*) variant causes a stop gained 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADCY5 NM_183357.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.92
• Publications: 0 publications found

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]

ADCY5 Gene-Disease associations (from GenCC):

• dyskinesia with orofacial involvement

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• dyskinesia with orofacial involvement, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: G2P
• neurodevelopmental disorder with hyperkinetic movements and dyskinesia

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial dyskinesia and facial myokymia

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• choreatic disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0291 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183357.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY5	NM_183357.3	MANE Select	c.3676C>T	p.Gln1226*	stop_gained	Exon 21 of 21	NP_899200.1	O95622-1
	ADCY5	NM_001378259.1		c.3751C>T	p.Gln1251*	stop_gained	Exon 22 of 22	NP_001365188.1	A0A8V8TP58
	ADCY5	NM_001199642.1		c.2626C>T	p.Gln876*	stop_gained	Exon 21 of 21	NP_001186571.1	O95622-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY5	ENST00000462833.6	TSL:1 MANE Select	c.3676C>T	p.Gln1226*	stop_gained	Exon 21 of 21	ENSP00000419361.1	O95622-1
	ADCY5	ENST00000850916.1		c.3838C>T	p.Gln1280*	stop_gained	Exon 21 of 21	ENSP00000520999.1	A0ABJ7H376
	ADCY5	ENST00000699718.1		c.3751C>T	p.Gln1251*	stop_gained	Exon 22 of 22	ENSP00000514543.1	A0A8V8TP58

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		7.9
Vest4		0.80
GERP RS		4.9
Mutation Taster		=2/198	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1553715806; hg19: chr3-123003565;