1-167810781-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_018417.6(ADCY10):c.4615C>T(p.Arg1539Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,614,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: ADCY10 NM_018417.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.54

Genes affected

ADCY10 (HGNC:21285): (adenylate cyclase 10) The protein encoded by this gene belongs to a distinct class of adenylyl cyclases that is soluble and insensitive to G protein or forskolin regulation. Activity of this protein is regulated by bicarbonate. Variation at this gene has been observed in patients with absorptive hypercalciuria. Alternatively spliced transcript variants encoding different isoforms have been observed. There is a pseudogene of this gene on chromosome 6. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05236435).
• BS2: High AC in GnomAd at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY10	NM_018417.6	c.4615C>T	p.Arg1539Trp	missense_variant	32/33	ENST00000367851.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY10	ENST00000367851.9	c.4615C>T	p.Arg1539Trp	missense_variant	32/33	1	NM_018417.6	P1
ADCY10	ENST00000367848.1	c.4339C>T	p.Arg1447Trp	missense_variant	32/33	1
ADCY10	ENST00000545172.5	c.4156C>T	p.Arg1386Trp	missense_variant	29/30	2
ADCY10	ENST00000485964.5	c.*1551C>T		3_prime_UTR_variant, NMD_transcript_variant	14/15	5

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000955 AC: 24 AN: 251424 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135880

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.0000413 AC XY: 30 AN XY: 727242

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74466

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.000174

ExAC AF: 0.0000906 AC: 11

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 17, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with ADCY10-related conditions. This variant is present in population databases (rs150827904, gnomAD 0.05%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1539 of the ADCY10 protein (p.Arg1539Trp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	15
Dann	Benign	0.97
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.052	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.99, 0.99	.;D;D
Vest4		0.30
MVP		0.072
MPC		0.29
ClinPred		0.11	T
GERP RS		-8.9
Varity_R		0.073
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs150827904; hg19: chr1-167780018;