3-123284684-C-T

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.3710G>A(p.Cys1237Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 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: 2.11

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 where missense usually causes diseases, ADCY5
• BP4: Computational evidence support a benign effect (MetaRNN=0.25566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY5	NM_183357.3	c.3710G>A	p.Cys1237Tyr	missense_variant	21/21	ENST00000462833.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY5	ENST00000462833.6	c.3710G>A	p.Cys1237Tyr	missense_variant	21/21	1	NM_183357.3	P1

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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ADCY5 protein function. This variant has not been reported in the literature in individuals affected with ADCY5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1237 of the ADCY5 protein (p.Cys1237Tyr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	21
Dann	Benign	0.80
DEOGEN2	Pathogenic	0.83	D;T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.3	D;D;D
REVEL	Uncertain	0.30
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.055	B;B;.
Vest4		0.067
MutPred		0.53		Gain of MoRF binding (P = 0.0674);.;.;
MVP		0.46
MPC		1.6
ClinPred		0.74	D
GERP RS		4.0
Varity_R		0.31
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr3-123003531;