3-123284706-C-T

Variant names:

• chr3-123284706-C-T
• NM_183357.3:c.3688G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_183357.3(ADCY5):​c.3688G>A​(p.Ala1230Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1230V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADCY5 NM_183357.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92

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 Uncertain_significance. Variant got 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1666871).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCY5	NM_183357.3	c.3688G>A	p.Ala1230Thr	missense_variant	Exon 21 of 21	ENST00000462833.6	NP_899200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADCY5	ENST00000462833.6	c.3688G>A	p.Ala1230Thr	missense_variant	Exon 21 of 21	1	NM_183357.3	ENSP00000419361.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3688G>A (p.A1230T) alteration is located in exon 21 (coding exon 21) of the ADCY5 gene. This alteration results from a G to A substitution at nucleotide position 3688, causing the alanine (A) at amino acid position 1230 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.0022
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.055	N;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.082
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.57	T;T;T
Polyphen		0.099	B;B;.
Vest4		0.39
MutPred		0.40		Gain of glycosylation at Y1225 (P = 0.0034);.;.;
MVP		0.46
MPC		0.97
ClinPred		0.68	D
GERP RS		4.9
Varity_R		0.089
gMVP		0.47

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-123003553; COSMIC: COSV59203141; COSMIC: COSV59203141;