7-45574614-C-A

Variant names:

• chr7-45574614-C-A
• rs1348282259
• NM_021116.4:c.71C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021116.4(ADCY1):​c.71C>A​(p.Ala24Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000683 in 146,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 31)
  • 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: 3.94
• Publications: 0 publications found

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]

ADCY1 Gene-Disease associations (from GenCC):

• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 44

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27427524).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021116.4. 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
	ADCY1	NM_021116.4	MANE Select	c.71C>A	p.Ala24Glu	missense	Exon 1 of 20	NP_066939.1	Q08828
	ADCY1	NM_001281768.2		c.-330-275C>A		intron	N/A	NP_001268697.1	C9J1J0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY1	ENST00000297323.12	TSL:1 MANE Select	c.71C>A	p.Ala24Glu	missense	Exon 1 of 20	ENSP00000297323.7	Q08828
	ADCY1	ENST00000920696.1		c.71C>A	p.Ala24Glu	missense	Exon 1 of 19	ENSP00000590755.1
	ADCY1	ENST00000432715.5	TSL:2	c.-330-275C>A		intron	N/A	ENSP00000392721.1	C9J1J0

Frequencies

GnomAD3 genomes AF: 0.00000683 AC: 1 AN: 146502 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1011180 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 476266

African (AFR) AF: 0.00 AC: 0 AN: 20432

American (AMR) AF: 0.00 AC: 0 AN: 6114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11252

East Asian (EAS) AF: 0.00 AC: 0 AN: 20134

South Asian (SAS) AF: 0.00 AC: 0 AN: 19072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2548

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 875500

Other (OTH) AF: 0.00 AC: 0 AN: 38528

GnomAD4 genome AF: 0.00000683 AC: 1 AN: 146502 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 71336

African (AFR) AF: 0.00 AC: 0 AN: 40560

American (AMR) AF: 0.00 AC: 0 AN: 14808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 4970

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66064

Other (OTH) AF: 0.00 AC: 0 AN: 2024

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.39	T
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.42	T
Polyphen		0.13	B
Vest4		0.33
MutPred		0.20		Gain of solvent accessibility (P = 0.0145)
MVP		0.76
MPC		1.4
ClinPred		0.50	T
GERP RS		2.9
PromoterAI		0.080	Neutral
Varity_R		0.42
gMVP		0.27
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs1348282259; hg19: chr7-45614213;