dbSNP rs13317079: ADCY5:c.*157G>T (chr3-123284451-C-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_183357.3(ADCY5):c.*157G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 1,234,800 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 47 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 32 hom. )

Consequence

ADCY5
NM_183357.3 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.420

Publications

6 publications found

Variant links:

Genes affected

ADCY5 (HGNC:236): (adenylate cyclase 5) This gene encodes a member of the membrane-bound adenylyl cyclase enzymes. Adenylyl cyclases mediate G protein-coupled receptor signaling through the synthesis of the second messenger cAMP. Activity of the encoded protein is stimulated by the Gs alpha subunit of G protein-coupled receptors and is inhibited by protein kinase A, calcium and Gi alpha subunits. Single nucleotide polymorphisms in this gene may be associated with low birth weight and type 2 diabetes. Alternatively spliced transcript variants that encode different isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

ADCY5 Gene-Disease associations (from GenCC):

dyskinesia with orofacial involvement
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
dyskinesia with orofacial involvement, autosomal dominant
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder
Inheritance: AD Classification: STRONG Submitted by: G2P
neurodevelopmental disorder with hyperkinetic movements and dyskinesia
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
familial dyskinesia and facial myokymia
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
choreatic disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ADCY5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 3-123284451-C-A is Benign according to our data. Variant chr3-123284451-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1197518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0137 (2087/152370) while in subpopulation AFR AF = 0.0461 (1919/41588). AF 95% confidence interval is 0.0444. There are 47 homozygotes in GnomAd4. There are 956 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 47 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183357.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ADCY5	NM_183357.3	MANE Select	c.*157G>T	3_prime_UTR	Exon 21 of 21	NP_899200.1	O95622-1
ADCY5	NM_001378259.1		c.*157G>T	3_prime_UTR	Exon 22 of 22	NP_001365188.1	A0A8V8TP58
ADCY5	NM_001199642.1		c.*157G>T	3_prime_UTR	Exon 21 of 21	NP_001186571.1	O95622-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ADCY5	ENST00000462833.6	TSL:1 MANE Select	c.*157G>T	3_prime_UTR	Exon 21 of 21	ENSP00000419361.1	O95622-1
ADCY5	ENST00000850916.1		c.*157G>T	3_prime_UTR	Exon 21 of 21	ENSP00000520999.1	A0ABJ7H376
ADCY5	ENST00000699718.1		c.*157G>T	3_prime_UTR	Exon 22 of 22	ENSP00000514543.1	A0A8V8TP58

Frequencies

GnomAD3 genomes

AF:

0.0137

AC:

2088

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0463

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00817

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.0105

GnomAD4 exome

AF:

0.00155

AC:

1683

AN:

1082430

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

740

AN XY:

534320

show subpopulations

African (AFR)

AF:

0.0489

AC:

1202

AN:

24580

American (AMR)

AF:

0.00349

AC:

AN:

22668

Ashkenazi Jewish (ASJ)

AF:

0.0000560

AC:

AN:

17854

East Asian (EAS)

AF:

0.0000285

AC:

AN:

35062

South Asian (SAS)

AF:

0.0000978

AC:

AN:

61328

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32520

Middle Eastern (MID)

AF:

0.00474

AC:

AN:

3166

European-Non Finnish (NFE)

AF:

0.000248

AC:

208

AN:

838414

Other (OTH)

AF:

0.00365

AC:

171

AN:

46838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

152

229

305

381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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

AF:

0.0137

AC:

2087

AN:

152370

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

956

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.0461

AC:

1919

AN:

41588

American (AMR)

AF:

0.00816

AC:

125

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68040

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

105

210

314

419

524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00877

Hom.:

Bravo

AF:

0.0156

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.83

PhyloP100

0.42

Mutation Taster

=100/0

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over