rs548282891

Variant names:

• chr3-123448242-C-T
• rs548282891
• NM_183357.3:c.304G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-123448242-C-T
• chr3-123448242-C-A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_183357.3(ADCY5):​c.304G>A​(p.Ala102Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000926 in 1,447,536 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A102A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (1 hom.)
• Consequence: ADCY5 NM_183357.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 3.31
• Publications: 1 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006801814).
• BP6: Variant 3-123448242-C-T is Benign according to our data. Variant chr3-123448242-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 390053.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000165 (25/151444) while in subpopulation AMR AF = 0.00158 (24/15214). AF 95% confidence interval is 0.00109. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.304G>A	p.Ala102Thr	missense	Exon 1 of 21	NP_899200.1	O95622-1
	ADCY5	NM_001378259.1		c.304G>A	p.Ala102Thr	missense	Exon 1 of 22	NP_001365188.1	A0A8V8TP58

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY5	ENST00000462833.6	TSL:1 MANE Select	c.304G>A	p.Ala102Thr	missense	Exon 1 of 21	ENSP00000419361.1	O95622-1
	ADCY5	ENST00000850916.1		c.466G>A	p.Ala156Thr	missense	Exon 1 of 21	ENSP00000520999.1	A0ABJ7H376
	ADCY5	ENST00000699718.1		c.304G>A	p.Ala102Thr	missense	Exon 1 of 22	ENSP00000514543.1	A0A8V8TP58

Frequencies

GnomAD3 genomes AF: 0.000172 AC: 26 AN: 151336 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00165

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000611 AC: 72 AN: 117794 AF XY: 0.000391

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000363

GnomAD4 exome AF: 0.0000841 AC: 109 AN: 1296092 Hom.: 1 Cov.: 29 AF XY: 0.0000749 AC XY: 48 AN XY: 640610

African (AFR) AF: 0.00 AC: 0 AN: 27076

American (AMR) AF: 0.00336 AC: 91 AN: 27108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22446

East Asian (EAS) AF: 0.00 AC: 0 AN: 29970

South Asian (SAS) AF: 0.00 AC: 0 AN: 66028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3990

European-Non Finnish (NFE) AF: 0.0000135 AC: 14 AN: 1034860

Other (OTH) AF: 0.0000763 AC: 4 AN: 52398

GnomAD4 genome AF: 0.000165 AC: 25 AN: 151444 Hom.: 0 Cov.: 32 AF XY: 0.000243 AC XY: 18 AN XY: 74014

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00158 AC: 24 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67852

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000283

ExAC AF: 0.000207 AC: 23

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	-	Dyskinesia with orofacial involvement, autosomal dominant (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.3
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.21
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.016	D
Polyphen		0.20	B
Vest4		0.25
MutPred		0.20		Gain of glycosylation at S101 (P = 0.0069)
MVP		0.71
MPC		0.86
ClinPred		0.10	T
GERP RS		1.9
Varity_R		0.26
gMVP		0.39
Mutation Taster		=74/26	polymorphism

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: rs548282891; hg19: chr3-123167089;