3-123416397-G-A

Variant names:

• chr3-123416397-G-A
• rs7641344
• NM_183357.3:c.1134+31015C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_183357.3(ADCY5):​c.1134+31015C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 1,450,452 control chromosomes in the GnomAD database, including 6,352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (1194 hom., cov: 32)
  • Exomes 𝑓: 0.032 (5158 hom.)
• Consequence: ADCY5 NM_183357.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.810
• Publications: 3 publications found

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, 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: Ambry Genetics, Orphanet
• choreatic disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 3-123416397-G-A is Benign according to our data. Variant chr3-123416397-G-A is described in ClinVar as Benign. ClinVar VariationId is 1260407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCY5	NM_183357.3	c.1134+31015C>T		intron_variant	Intron 1 of 20	ENST00000462833.6	NP_899200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADCY5	ENST00000462833.6	c.1134+31015C>T		intron_variant	Intron 1 of 20	1	NM_183357.3	ENSP00000419361.1

Frequencies

GnomAD3 genomes AF: 0.0819 AC: 12452 AN: 152100 Hom.: 1182 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0890

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.00416

Gnomad OTH AF: 0.0713

GnomAD4 exome AF: 0.0321 AC: 41651 AN: 1298234 Hom.: 5158 AF XY: 0.0347 AC XY: 22012 AN XY: 633810

African (AFR) AF: 0.195 AC: 5810 AN: 29772

American (AMR) AF: 0.115 AC: 3562 AN: 31042

Ashkenazi Jewish (ASJ) AF: 0.00876 AC: 186 AN: 21242

East Asian (EAS) AF: 0.406 AC: 14155 AN: 34860

South Asian (SAS) AF: 0.167 AC: 11324 AN: 67710

European-Finnish (FIN) AF: 0.00943 AC: 294 AN: 31166

Middle Eastern (MID) AF: 0.0253 AC: 136 AN: 5372

European-Non Finnish (NFE) AF: 0.00320 AC: 3271 AN: 1022674

Other (OTH) AF: 0.0536 AC: 2913 AN: 54396

GnomAD4 genome AF: 0.0820 AC: 12480 AN: 152218 Hom.: 1194 Cov.: 32 AF XY: 0.0851 AC XY: 6335 AN XY: 74420

African (AFR) AF: 0.186 AC: 7710 AN: 41520

American (AMR) AF: 0.0889 AC: 1360 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 38 AN: 3472

East Asian (EAS) AF: 0.358 AC: 1849 AN: 5160

South Asian (SAS) AF: 0.194 AC: 937 AN: 4818

European-Finnish (FIN) AF: 0.0106 AC: 112 AN: 10604

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.00415 AC: 282 AN: 68030

Other (OTH) AF: 0.0810 AC: 171 AN: 2112

Alfa AF: 0.0385 Hom.: 122

Bravo AF: 0.0903

Asia WGS AF: 0.320 AC: 1108 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.32
DANN	Benign	0.41
PhyloP100		-0.81
PromoterAI		0.023	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7641344; hg19: chr3-123135244;