rs77524127

Positions:

• chr7-45662054-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021116.4(ADCY1):​c.1450-5G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,613,326 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (16 hom., cov: 32)
  • Exomes 𝑓: 0.012 (153 hom.)
• Consequence: ADCY1 NM_021116.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003212
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.37

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-45662054-G-T is Benign according to our data. Variant chr7-45662054-G-T is described in ClinVar as [Benign]. Clinvar id is 517524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0121 (17612/1461070) while in subpopulation MID AF= 0.0222 (128/5758). AF 95% confidence interval is 0.0191. There are 153 homozygotes in gnomad4_exome. There are 8738 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADCY1	NM_021116.4	c.1450-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000297323.12	NP_066939.1
ADCY1	NM_001281768.2	c.775-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001268697.1
ADCY1	XM_005249584.4	c.1450-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_005249641.1
ADCY1	XM_005249585.3	c.1450-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_005249642.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADCY1	ENST00000297323.12	c.1450-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_021116.4	ENSP00000297323	P1
ADCY1	ENST00000432715.5	c.775-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000392721
ADCY1	ENST00000621543.1	c.775-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000479770
ADCY1	ENST00000646653.1	n.391-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1747 AN: 152138 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00719

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0501

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0126 AC: 3152 AN: 250766 Hom.: 42 AF XY: 0.0125 AC XY: 1699 AN XY: 135474

Gnomad AFR exome AF: 0.00868

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.0473

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00716

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0121 AC: 17612 AN: 1461070 Hom.: 153 Cov.: 31 AF XY: 0.0120 AC XY: 8738 AN XY: 726768

Gnomad4 AFR exome AF: 0.00780

Gnomad4 AMR exome AF: 0.0105

Gnomad4 ASJ exome AF: 0.0452

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00715

Gnomad4 FIN exome AF: 0.0109

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.0143

GnomAD4 genome AF: 0.0115 AC: 1745 AN: 152256 Hom.: 16 Cov.: 32 AF XY: 0.0118 AC XY: 882 AN XY: 74442

Gnomad4 AFR AF: 0.00715

Gnomad4 AMR AF: 0.0117

Gnomad4 ASJ AF: 0.0501

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00499

Gnomad4 FIN AF: 0.0116

Gnomad4 NFE AF: 0.0133

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0152 Hom.: 9

Bravo AF: 0.0115

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0165

EpiControl AF: 0.0175

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

c.1450-5G>T in intron 7 of ADCY1: This variant is not expected to have clinical significance because it has been identified in 1.66% (1102/66292) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs77524127). -

ADCY1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.073
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0060
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

LitVar

Other links and lift over

dbSNP: rs77524127; hg19: chr7-45701653;