NM_001115.3:c.3429G>C

Variant names:

• chr8-130780717-C-G
• NM_001115.3:c.3429G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001115.3(ADCY8):​c.3429G>C​(p.Gln1143His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADCY8 NM_001115.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00600

Genes affected

ADCY8 (HGNC:239): (adenylate cyclase 8) Adenylate cyclase is a membrane bound enzyme that catalyses the formation of cyclic AMP from ATP. The enzymatic activity is under the control of several hormones, and different polypeptides participate in the transduction of the signal from the receptor to the catalytic moiety. Stimulatory or inhibitory receptors (Rs and Ri) interact with G proteins (Gs and Gi) that exhibit GTPase activity and they modulate the activity of the catalytic subunit of the adenylyl cyclase [provided by RefSeq, Jul 2008]

ACMG classification

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=0.15543148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCY8	NM_001115.3	c.3429G>C	p.Gln1143His	missense_variant	Exon 18 of 18	ENST00000286355.10	NP_001106.1
ADCY8	XM_005250769.4	c.3339G>C	p.Gln1113His	missense_variant	Exon 17 of 17		XP_005250826.1
ADCY8	XM_006716501.4	c.3231G>C	p.Gln1077His	missense_variant	Exon 17 of 17		XP_006716564.1
ADCY8	XM_017013006.2	c.3141G>C	p.Gln1047His	missense_variant	Exon 16 of 16		XP_016868495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADCY8	ENST00000286355.10	c.3429G>C	p.Gln1143His	missense_variant	Exon 18 of 18	1	NM_001115.3	ENSP00000286355.5
ADCY8	ENST00000377928.7	c.3036G>C	p.Gln1012His	missense_variant	Exon 15 of 15	1		ENSP00000367161.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3429G>C (p.Q1143H) alteration is located in exon 18 (coding exon 18) of the ADCY8 gene. This alteration results from a G to C substitution at nucleotide position 3429, causing the glutamine (Q) at amino acid position 1143 to be replaced by a histidine (H). 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	0.13
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.15	N;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.20
Sift	Benign	0.10	T;T
Sift4G	Benign	0.084	T;T
Polyphen		0.013	B;B
Vest4		0.42
MutPred		0.60		Gain of helix (P = 0.132);.;
MVP		0.71
MPC		0.39
ClinPred		0.36	T
GERP RS		2.0
Varity_R		0.090
gMVP		0.54

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: chr8-131792963;