Variant 14-24323382-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001198568.2(ADCY4):c.2119T>C(p.Trp707Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000086 in 1,557,360 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: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

ADCY4
NM_001198568.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.96

Variant links:

Genes affected

ADCY4 (HGNC:235): (adenylate cyclase 4) This gene encodes a member of the family of adenylate cyclases, which are membrane-associated enzymes that catalyze the formation of the secondary messenger cyclic adenosine monophosphate (cAMP). Mouse studies show that adenylate cyclase 4, along with adenylate cyclases 2 and 3, is expressed in olfactory cilia, suggesting that several different adenylate cyclases may couple to olfactory receptors and that there may be multiple receptor-mediated mechanisms for the generation of cAMP signals. Alternative splicing results in transcript variants. [provided by RefSeq, Nov 2010]

ADCY4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1479316).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ADCY4	NM_001198568.2 linkuse as main transcript	c.2119T>C	p.Trp707Arg	missense_variant	17/25	ENST00000418030.7
ADCY4	NM_001198592.2 linkuse as main transcript	c.2119T>C	p.Trp707Arg	missense_variant	18/26
ADCY4	NM_139247.4 linkuse as main transcript	c.2119T>C	p.Trp707Arg	missense_variant	18/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY4	ENST00000418030.7 linkuse as main transcript	c.2119T>C	p.Trp707Arg	missense_variant	17/25	1	NM_001198568.2	P1	Q8NFM4-1

Frequencies

GnomAD3 genomes

AF:

0.000467

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00465

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000279

AC:

AN:

168624

Hom.:

AF XY:

0.000236

AC XY:

AN XY:

88862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00170

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:

0.00

Gnomad OTH exome

AF:

0.000642

GnomAD4 exome

AF:

0.0000448

AC:

AN:

1405182

Hom.:

Cov.:

AF XY:

0.0000433

AC XY:

AN XY:

693582

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00169

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.000467

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000632

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00465

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.000389

ExAC

AF:

0.0000262

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2022

The c.2119T>C (p.W707R) alteration is located in exon 17 (coding exon 17) of the ADCY4 gene. This alteration results from a T to C substitution at nucleotide position 2119, causing the tryptophan (W) at amino acid position 707 to be replaced by an arginine (R). 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

0.31

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Uncertain

0.090

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;T;T

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.044

FATHMM_MKL

Benign

0.33

M_CAP

Benign

0.032

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.1

L;L;L

MutationTaster

Benign

0.93

D;D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.35

N;N;N

REVEL

Uncertain

0.39

Sift

Benign

0.35

T;T;T

Sift4G

Benign

0.38

T;T;T

Polyphen

0.0060

B;B;B

Vest4

0.79

MutPred

0.55

Gain of disorder (P = 0.0026);Gain of disorder (P = 0.0026);Gain of disorder (P = 0.0026);

MVP

0.84

MPC

0.58

ClinPred

0.044

GERP RS

4.2

Varity_R

0.078

gMVP

0.49

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

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