14-24318556-T-C

Variant names:

• chr14-24318556-T-C
• NM_001198568.2:c.3094A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001198568.2(ADCY4):​c.3094A>G​(p.Thr1032Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADCY4 NM_001198568.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.25

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCY4	NM_001198568.2	c.3094A>G	p.Thr1032Ala	missense_variant	Exon 25 of 25	ENST00000418030.7	NP_001185497.1
ADCY4	NM_001198592.2	c.3094A>G	p.Thr1032Ala	missense_variant	Exon 26 of 26		NP_001185521.1
ADCY4	NM_139247.4	c.3094A>G	p.Thr1032Ala	missense_variant	Exon 26 of 26		NP_640340.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADCY4	ENST00000418030.7	c.3094A>G	p.Thr1032Ala	missense_variant	Exon 25 of 25	1	NM_001198568.2	ENSP00000393177.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3094A>G (p.T1032A) alteration is located in exon 25 (coding exon 25) of the ADCY4 gene. This alteration results from a A to G substitution at nucleotide position 3094, causing the threonine (T) at amino acid position 1032 to be replaced by an alanine (A). 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	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;D;D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	2.0	M;M;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.1	D;D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.23	B;B;B
Vest4		0.74
MutPred		0.69		Gain of catalytic residue at Q1037 (P = 0);Gain of catalytic residue at Q1037 (P = 0);Gain of catalytic residue at Q1037 (P = 0);
MVP		0.95
MPC		1.1
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.70
gMVP		0.94

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-24787762;