rs1553333167

Variant names:

• chr2-24824537-C-T
• rs1553333167
• NM_004036.5:c.2578-1G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-24824537-C-T
• chr2-24824537-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_004036.5(ADCY3):​c.2578-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADCY3 NM_004036.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 7.80
• Publications: 1 publications found

Genes affected

ADCY3 (HGNC:234): (adenylate cyclase 3) This gene encodes adenylyl cyclase 3 which is a membrane-associated enzyme and catalyzes the formation of the secondary messenger cyclic adenosine monophosphate (cAMP). This protein appears to be widely expressed in various human tissues and may be involved in a number of physiological and pathophysiological metabolic processes. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

ADCY3 Gene-Disease associations (from GenCC):

• body mass index quantitative trait locus 19

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.04628821 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5, offset of 4, new splice context is: ttgtctgtgtctgtaagtAGaaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004036.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY3	NM_004036.5	MANE Select	c.2578-1G>A		splice_acceptor intron	N/A	NP_004027.2	O60266-1
	ADCY3	NM_001377128.1		c.2644-1G>A		splice_acceptor intron	N/A	NP_001364057.1
	ADCY3	NM_001320613.2		c.2581-1G>A		splice_acceptor intron	N/A	NP_001307542.1	A0A0A0MSC1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY3	ENST00000679454.1	MANE Select	c.2578-1G>A		splice_acceptor intron	N/A	ENSP00000505261.1	O60266-1
	ADCY3	ENST00000405392.6	TSL:1	c.2581-1G>A		splice_acceptor intron	N/A	ENSP00000384484.2	A0A0A0MSC1
	ADCY3	ENST00000260600.9	TSL:1	c.2578-1G>A		splice_acceptor intron	N/A	ENSP00000260600.5	O60266-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 19 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.8
GERP RS		5.1
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.50		Position offset: -5
DS_AL_spliceai		0.99		Position offset: -1

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

Other links and lift over

dbSNP: rs1553333167; hg19: chr2-25047406;