3-123284618-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS1

The NM_183357.3(ADCY5):c.3776C>T(p.Pro1259Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000873 in 1,614,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1259P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: ADCY5 NM_183357.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.55

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 Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ADCY5
• BP4: Computational evidence support a benign effect (MetaRNN=0.014128625).
• BP6: Variant 3-123284618-G-A is Benign according to our data. Variant chr3-123284618-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 794055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000118 (18/152356) while in subpopulation EAS AF= 0.0027 (14/5184). AF 95% confidence interval is 0.00163. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY5	NM_183357.3	c.3776C>T	p.Pro1259Leu	missense_variant	21/21	ENST00000462833.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY5	ENST00000462833.6	c.3776C>T	p.Pro1259Leu	missense_variant	21/21	1	NM_183357.3	P1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000239 AC: 60 AN: 251414 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00234

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000841 AC: 123 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.0000825 AC XY: 60 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00174

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74506

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000401 Hom.: 0

Bravo AF: 0.000140

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

ADCY5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Uncertain	0.018	D
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.82	P;P;.
Vest4		0.39
MVP		0.80
MPC		1.8
ClinPred		0.15	T
GERP RS		5.0
Varity_R		0.22
gMVP		0.55

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

LitVar

Other links and lift over

dbSNP: rs117446067; hg19: chr3-123003465; COSMIC: COSV59194272; COSMIC: COSV59194272;