3-123287606-A-G

Variant names:

• chr3-123287606-A-G
• rs6777397
• NM_183357.3:c.3533-797T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_183357.3(ADCY5):​c.3533-797T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.415 in 150,408 control chromosomes in the GnomAD database, including 13,449 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.41 (13449 hom., cov: 33)
• Consequence: ADCY5 NM_183357.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.408
• Publications: 7 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, 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: Ambry Genetics, Orphanet
• choreatic disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY5	NM_183357.3	MANE Select	c.3533-797T>C		intron	N/A	NP_899200.1
	ADCY5	NM_001378259.1		c.3608-797T>C		intron	N/A	NP_001365188.1
	ADCY5	NM_001199642.1		c.2483-797T>C		intron	N/A	NP_001186571.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY5	ENST00000462833.6	TSL:1 MANE Select	c.3533-797T>C		intron	N/A	ENSP00000419361.1
	ADCY5	ENST00000850916.1		c.3695-797T>C		intron	N/A	ENSP00000520999.1
	ADCY5	ENST00000699718.1		c.3608-797T>C		intron	N/A	ENSP00000514543.1

Frequencies

GnomAD3 genomes AF: 0.415 AC: 62356 AN: 150286 Hom.: 13435 Cov.: 33

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.811

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.427

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.415 AC: 62406 AN: 150408 Hom.: 13449 Cov.: 33 AF XY: 0.425 AC XY: 31267 AN XY: 73534

African (AFR) AF: 0.373 AC: 14883 AN: 39918

American (AMR) AF: 0.458 AC: 6973 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 1732 AN: 3470

East Asian (EAS) AF: 0.811 AC: 4198 AN: 5174

South Asian (SAS) AF: 0.521 AC: 2509 AN: 4818

European-Finnish (FIN) AF: 0.460 AC: 4864 AN: 10570

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.379 AC: 25749 AN: 67954

Other (OTH) AF: 0.433 AC: 905 AN: 2090

Alfa AF: 0.385 Hom.: 15881

Bravo AF: 0.410

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.1
DANN	Benign	0.77
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6777397; hg19: chr3-123006453;