chr14-24319837-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001198568.2(ADCY4):c.2638C>T(p.Pro880Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000129 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
ADCY4
NM_001198568.2 missense
NM_001198568.2 missense
Scores
4
7
7
Clinical Significance
Conservation
PhyloP100: 5.85
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 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.77
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADCY4 | NM_001198568.2 | c.2638C>T | p.Pro880Ser | missense_variant | 21/25 | ENST00000418030.7 | |
ADCY4 | NM_001198592.2 | c.2638C>T | p.Pro880Ser | missense_variant | 22/26 | ||
ADCY4 | NM_139247.4 | c.2638C>T | p.Pro880Ser | missense_variant | 22/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADCY4 | ENST00000418030.7 | c.2638C>T | p.Pro880Ser | missense_variant | 21/25 | 1 | NM_001198568.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152154Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000107 AC: 27AN: 251414Hom.: 0 AF XY: 0.0000883 AC XY: 12AN XY: 135888
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GnomAD4 exome AF: 0.000129 AC: 188AN: 1461814Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 98AN XY: 727212
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GnomAD4 genome AF: 0.000131 AC: 20AN: 152272Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74442
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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 | Jul 27, 2023 | The c.2638C>T (p.P880S) alteration is located in exon 21 (coding exon 21) of the ADCY4 gene. This alteration results from a C to T substitution at nucleotide position 2638, causing the proline (P) at amino acid position 880 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Benign
Sift
Uncertain
D;D;D
Sift4G
Benign
T;T;T
Polyphen
P;P;P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at