rs587777497

Positions:

• chr7-45713747-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_021116.4(ADCY1):​c.3112C>T​(p.Arg1038*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000159 in 628,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: ADCY1 NM_021116.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 1.96

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 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0738 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-45713747-C-T is Pathogenic according to our data. Variant chr7-45713747-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 139587.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-45713747-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADCY1	NM_021116.4	c.3112C>T	p.Arg1038*	stop_gained	20/20	ENST00000297323.12	NP_066939.1
ADCY1	XM_005249584.4	c.*47C>T		3_prime_UTR_variant	19/19		XP_005249641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADCY1	ENST00000297323.12	c.3112C>T	p.Arg1038*	stop_gained	20/20	1	NM_021116.4	ENSP00000297323.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000159 AC: 1 AN: 628452 Hom.: 0 Cov.: 0 AF XY: 0.00000292 AC XY: 1 AN XY: 342378

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000143

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 44 Pathogenic:2

Pathogenic, no assertion criteria provided	research	Department of Molecular and Human Genetics, Baylor College of Medicine	Nov 20, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 15, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.84	D
Vest4		0.76
ClinPred		1.0	D
GERP RS		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587777497; hg19: chr7-45753346; COSMIC: COSV52038469;