rs11708067

Variant names:

• chr3-123346931-A-G
• rs11708067
• NM_183357.3:c.1406+851T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_183357.3(ADCY5):​c.1406+851T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 151,998 control chromosomes in the GnomAD database, including 3,061 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 0.19 (3061 hom., cov: 31)
• Consequence: ADCY5 NM_183357.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.42
• Publications: 244 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCY5	NM_183357.3	c.1406+851T>C		intron_variant	Intron 3 of 20	ENST00000462833.6	NP_899200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADCY5	ENST00000462833.6	c.1406+851T>C		intron_variant	Intron 3 of 20	1	NM_183357.3	ENSP00000419361.1

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29294 AN: 151878 Hom.: 3057 Cov.: 31

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.165

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

GnomAD4 genome AF: 0.193 AC: 29310 AN: 151998 Hom.: 3061 Cov.: 31 AF XY: 0.189 AC XY: 14066 AN XY: 74306

African (AFR) AF: 0.151 AC: 6258 AN: 41470

American (AMR) AF: 0.261 AC: 3986 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 569 AN: 3468

East Asian (EAS) AF: 0.00271 AC: 14 AN: 5164

South Asian (SAS) AF: 0.199 AC: 956 AN: 4812

European-Finnish (FIN) AF: 0.161 AC: 1701 AN: 10550

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15269 AN: 67948

Other (OTH) AF: 0.162 AC: 341 AN: 2106

Alfa AF: 0.208 Hom.: 14631

Bravo AF: 0.196

Asia WGS AF: 0.0960 AC: 332 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Benign	0.69
PhyloP100		2.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs11708067; hg19: chr3-123065778;