chr7-45574930-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_021116.4(ADCY1):​c.387C>A​(p.Phe129Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ADCY1
NM_021116.4 missense

Scores

3
4
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.40
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ADCY1. . Gene score misZ 4.3801 (greater than the threshold 3.09). Trascript score misZ 4.6991 (greater than threshold 3.09). GenCC has associacion of gene with hearing loss, autosomal recessive, autosomal recessive nonsyndromic hearing loss 44.
BP4
Computational evidence support a benign effect (MetaRNN=0.41325405).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ADCY1NM_021116.4 linkuse as main transcriptc.387C>A p.Phe129Leu missense_variant 1/20 ENST00000297323.12 NP_066939.1
ADCY1XM_005249584.4 linkuse as main transcriptc.387C>A p.Phe129Leu missense_variant 1/19 XP_005249641.1
ADCY1XM_005249585.3 linkuse as main transcriptc.387C>A p.Phe129Leu missense_variant 1/9 XP_005249642.1
ADCY1NM_001281768.2 linkuse as main transcriptc.-289C>A 5_prime_UTR_variant 2/10 NP_001268697.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ADCY1ENST00000297323.12 linkuse as main transcriptc.387C>A p.Phe129Leu missense_variant 1/201 NM_021116.4 ENSP00000297323 P1
ADCY1ENST00000432715.5 linkuse as main transcriptc.-289C>A 5_prime_UTR_variant 2/102 ENSP00000392721
ADCY1ENST00000621543.1 linkuse as main transcriptc.-289C>A 5_prime_UTR_variant 1/95 ENSP00000479770

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000411
AC:
1
AN:
243438
Hom.:
0
AF XY:
0.00000749
AC XY:
1
AN XY:
133536
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1459700
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
726222
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 27, 2022The c.387C>A (p.F129L) alteration is located in exon 1 (coding exon 1) of the ADCY1 gene. This alteration results from a C to A substitution at nucleotide position 387, causing the phenylalanine (F) at amino acid position 129 to be replaced by a leucine (L). 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
Pathogenic
0.93
BayesDel_addAF
Benign
-0.056
T
BayesDel_noAF
Benign
-0.22
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
T
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.13
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.82
T
M_CAP
Pathogenic
0.34
D
MetaRNN
Benign
0.41
T
MetaSVM
Benign
-0.66
T
MutationAssessor
Uncertain
2.0
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.95
D
PROVEAN
Benign
-1.8
N
REVEL
Uncertain
0.41
Sift
Benign
0.36
T
Sift4G
Benign
0.26
T
Polyphen
0.64
P
Vest4
0.39
MutPred
0.62
Loss of catalytic residue at F129 (P = 0.0639);
MVP
0.67
MPC
1.4
ClinPred
0.52
D
GERP RS
2.6
Varity_R
0.35
gMVP
0.72

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1035746347; hg19: chr7-45614529; API