7-45574559-CGCGGCGGAGGCG-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_021116.4(ADCY1):c.32_43del(p.Gly11_Gly14del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 977,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ADCY1 NM_021116.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.64

Genes affected

ADCY1 (HGNC:232): (adenylate cyclase 1) This gene encodes a member of the of adenylate cyclase gene family that is primarily expressed in the brain. This protein is regulated by calcium/calmodulin concentration and may be involved in brain development. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_021116.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY1	NM_021116.4	c.32_43del	p.Gly11_Gly14del	inframe_deletion	1/20	ENST00000297323.12
ADCY1	XM_005249584.4	c.32_43del	p.Gly11_Gly14del	inframe_deletion	1/19
ADCY1	XM_005249585.3	c.32_43del	p.Gly11_Gly14del	inframe_deletion	1/9
ADCY1	NM_001281768.2	c.-330-314_-330-303del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY1	ENST00000297323.12	c.32_43del	p.Gly11_Gly14del	inframe_deletion	1/20	1	NM_021116.4	P1
ADCY1	ENST00000432715.5	c.-330-314_-330-303del		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.000314 AC: 45 AN: 143096 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000402

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000825

Gnomad ASJ AF: 0.00119

Gnomad EAS AF: 0.000417

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000139

Gnomad OTH AF: 0.00100

GnomAD4 exome AF: 0.000108 AC: 90 AN: 833886 Hom.: 0 AF XY: 0.000117 AC XY: 45 AN XY: 385172

Gnomad4 AFR exome AF: 0.000253

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00116

Gnomad4 EAS exome AF: 0.000275

Gnomad4 SAS exome AF: 0.0000589

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000919

Gnomad4 OTH exome AF: 0.000293

GnomAD4 genome AF: 0.000314 AC: 45 AN: 143132 Hom.: 0 Cov.: 31 AF XY: 0.000287 AC XY: 20 AN XY: 69580

Gnomad4 AFR AF: 0.000401

Gnomad4 AMR AF: 0.000824

Gnomad4 ASJ AF: 0.00119

Gnomad4 EAS AF: 0.000419

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000139

Gnomad4 OTH AF: 0.000995

Alfa AF: 0.000216 Hom.: 0

Bravo AF: 0.000246

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

Jul 14, 2023

This variant, c.32_43del, results in the deletion of 4 amino acid(s) of the ADCY1 protein (p.Gly11_Gly14del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ADCY1-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs968371618; hg19: chr7-45614158;