7-45574716-A-G

Variant names:

• chr7-45574716-A-G
• rs1478175668
• NM_021116.4:c.173A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021116.4(ADCY1):​c.173A>G​(p.Gln58Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADCY1 NM_021116.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.38

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCY1	NM_021116.4	c.173A>G	p.Gln58Arg	missense_variant	Exon 1 of 20	ENST00000297323.12	NP_066939.1
ADCY1	XM_005249584.4	c.173A>G	p.Gln58Arg	missense_variant	Exon 1 of 19		XP_005249641.1
ADCY1	XM_005249585.3	c.173A>G	p.Gln58Arg	missense_variant	Exon 1 of 9		XP_005249642.1
ADCY1	NM_001281768.2	c.-330-173A>G		intron_variant	Intron 1 of 9		NP_001268697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADCY1	ENST00000297323.12	c.173A>G	p.Gln58Arg	missense_variant	Exon 1 of 20	1	NM_021116.4	ENSP00000297323.7
ADCY1	ENST00000432715.5	c.-330-173A>G		intron_variant	Intron 1 of 9	2		ENSP00000392721.1
ADCY1	ENST00000621543.1	c.-503A>G		upstream_gene_variant		5		ENSP00000479770.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1258616 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 618170

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.173A>G (p.Q58R) alteration is located in exon 1 (coding exon 1) of the ADCY1 gene. This alteration results from a A to G substitution at nucleotide position 173, causing the glutamine (Q) at amino acid position 58 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.73	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.7	L
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.58
Sift	Benign	0.22	T
Sift4G	Benign	0.33	T
Polyphen		0.99	D
Vest4		0.42
MutPred		0.56		Gain of methylation at Q58 (P = 0.0366);
MVP		0.91
MPC		2.5
ClinPred		0.97	D
GERP RS		2.8
Varity_R		0.33
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs1478175668; hg19: chr7-45614315;