chr14-24319193-C-T

Variant summary

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

The NM_001198568.2(ADCY4):​c.2861G>A​(p.Ser954Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. S954G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ADCY4
NM_001198568.2 missense

Scores

2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.284
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]

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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=0.1744298).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADCY4NM_001198568.2 linkc.2861G>A p.Ser954Asn missense_variant Exon 23 of 25 ENST00000418030.7 NP_001185497.1 Q8NFM4-1
ADCY4NM_001198592.2 linkc.2861G>A p.Ser954Asn missense_variant Exon 24 of 26 NP_001185521.1 Q8NFM4-1Q86TZ7
ADCY4NM_139247.4 linkc.2861G>A p.Ser954Asn missense_variant Exon 24 of 26 NP_640340.2 Q8NFM4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADCY4ENST00000418030.7 linkc.2861G>A p.Ser954Asn missense_variant Exon 23 of 25 1 NM_001198568.2 ENSP00000393177.2 Q8NFM4-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251310
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135828
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461848
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000508
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 26, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2861G>A (p.S954N) alteration is located in exon 23 (coding exon 23) of the ADCY4 gene. This alteration results from a G to A substitution at nucleotide position 2861, causing the serine (S) at amino acid position 954 to be replaced by an asparagine (N). 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
0.10
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.75
CADD
Benign
19
DANN
Benign
0.93
DEOGEN2
Benign
0.30
T;T;T
Eigen
Benign
-0.38
Eigen_PC
Benign
-0.18
FATHMM_MKL
Uncertain
0.78
D
M_CAP
Benign
0.0026
T
MetaRNN
Benign
0.17
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.39
N;N;N
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-1.2
N;N;N
REVEL
Benign
0.078
Sift
Benign
0.53
T;T;T
Sift4G
Benign
0.50
T;T;T
Polyphen
0.0
B;B;B
Vest4
0.34
MutPred
0.54
Gain of catalytic residue at H955 (P = 9e-04);Gain of catalytic residue at H955 (P = 9e-04);Gain of catalytic residue at H955 (P = 9e-04);
MVP
0.63
MPC
0.31
ClinPred
0.12
T
GERP RS
3.9
Varity_R
0.063
gMVP
0.51

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.

Other links and lift over

dbSNP: rs1268323150; hg19: chr14-24788399; API