Variant 3-123284630-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_183357.3(ADCY5):c.3764A>G(p.Asn1255Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ADCY5
NM_183357.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.90

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ADCY5. . Gene score misZ: 3.4043 (greater than the threshold 3.09). Trascript score misZ: 4.4657 (greater than threshold 3.09). The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 45 curated benign missense variants. GenCC has associacion of the gene with 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=0.23927999).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADCY5	NM_183357.3 link	c.3764A>G	p.Asn1255Ser	missense_variant	21/21	ENST00000462833.6	NP_899200.1	O95622-1A0A384P5Q5B7Z2C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADCY5	ENST00000462833.6 link	c.3764A>G	p.Asn1255Ser	missense_variant	21/21	1	NM_183357.3	ENSP00000419361.1		O95622-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251474

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The c.3764A>G (p.N1255S) alteration is located in exon 21 (coding exon 21) of the ADCY5 gene. This alteration results from a A to G substitution at nucleotide position 3764, causing the asparagine (N) at amino acid position 1255 to be replaced by a serine (S). 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

0.091

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.034

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.056

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.0

L;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.8

N;N;N

REVEL

Benign

0.26

Sift

Benign

0.071

T;T;T

Sift4G

Benign

0.57

T;T;T

Polyphen

0.029

B;B;.

Vest4

0.32

MutPred

0.42

Loss of glycosylation at P1259 (P = 0.0192);.;.;

MVP

0.77

MPC

0.78

ClinPred

0.44

GERP RS

5.0

Varity_R

0.11

gMVP

0.43

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over