Genetic Variant NM_001198568.2:c.2576G>T (chr14-24322076-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001198568.2(ADCY4):c.2576G>T(p.Arg859Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R859Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ADCY4
NM_001198568.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.42

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4104357).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001198568.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADCY4	NM_001198568.2	MANE Select	c.2576G>T	p.Arg859Leu	missense	Exon 20 of 25	NP_001185497.1	Q8NFM4-1
ADCY4	NM_001198592.2		c.2576G>T	p.Arg859Leu	missense	Exon 21 of 26	NP_001185521.1	Q8NFM4-1
ADCY4	NM_139247.4		c.2576G>T	p.Arg859Leu	missense	Exon 21 of 26	NP_640340.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADCY4	ENST00000418030.7	TSL:1 MANE Select	c.2576G>T	p.Arg859Leu	missense	Exon 20 of 25	ENSP00000393177.2	Q8NFM4-1
ADCY4	ENST00000554068.6	TSL:1	c.2576G>T	p.Arg859Leu	missense	Exon 21 of 26	ENSP00000452250.2	Q8NFM4-1
ADCY4	ENST00000554781.5	TSL:1	n.*1258G>T		non_coding_transcript_exon	Exon 20 of 25	ENSP00000450477.1	G3V258

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459914

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726022

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39648

South Asian (SAS)

AF:

0.00

AC:

AN:

86176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110506

Other (OTH)

AF:

0.00

AC:

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Benign

-0.072

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.023

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.59

PhyloP100

1.4

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.4

REVEL

Benign

0.29

Sift

Benign

0.27

Sift4G

Benign

0.17

Polyphen

0.039

Vest4

0.60

MutPred

0.47

Gain of catalytic residue at L864 (P = 0.002)

MVP

0.85

MPC

1.2

ClinPred

0.75

GERP RS

5.3

Varity_R

0.12

gMVP

0.61

Mutation Taster

=64/36

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over