chr16-3965901-C-A

Position:

• chr16-3965901-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001116.4(ADCY9):​c.3936G>T​(p.Trp1312Cys) 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: 33)
• Consequence: ADCY9 NM_001116.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.892

Genes affected

ADCY9 (HGNC:240): (adenylate cyclase 9) Adenylate cyclase is a membrane bound enzyme that catalyses the formation of cyclic AMP from ATP. It is regulated by a family of G protein-coupled receptors, protein kinases, and calcium. The type 9 adenylyl cyclase is a widely distributed adenylyl cyclase, and it is stimulated by beta-adrenergic receptor activation but is insensitive to forskolin, calcium, and somatostatin. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30801123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY9	NM_001116.4	c.3936G>T	p.Trp1312Cys	missense_variant	11/11	ENST00000294016.8
ADCY9	XM_005255079.4	c.3993G>T	p.Trp1331Cys	missense_variant	11/11
ADCY9	XM_011522353.3	c.2927+8768G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY9	ENST00000294016.8	c.3936G>T	p.Trp1312Cys	missense_variant	11/11	1	NM_001116.4	P1
ADCY9	ENST00000576936.5	c.567+8768G>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2024

The c.3936G>T (p.W1312C) alteration is located in exon 11 (coding exon 10) of the ADCY9 gene. This alteration results from a G to T substitution at nucleotide position 3936, causing the tryptophan (W) at amino acid position 1312 to be replaced by a cysteine (C). 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	0.16
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.035	D
Polyphen		0.84	P
Vest4		0.31
MutPred		0.30		Gain of catalytic residue at P1311 (P = 0.0073);
MVP		0.46
MPC		1.1
ClinPred		0.58	D
GERP RS		5.7
Varity_R		0.17
gMVP		0.21

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: chr16-4015902;