Variant 7-45574930-C-A details in Genebe, Genetics Data Aggregator

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

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]

ADCY1 links:

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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
ADCY1	NM_021116.4 linkuse as main transcript	c.387C>A	p.Phe129Leu	missense_variant	1/20	ENST00000297323.12	NP_066939.1
ADCY1	XM_005249584.4 linkuse as main transcript	c.387C>A	p.Phe129Leu	missense_variant	1/19		XP_005249641.1
ADCY1	XM_005249585.3 linkuse as main transcript	c.387C>A	p.Phe129Leu	missense_variant	1/9		XP_005249642.1
ADCY1	NM_001281768.2 linkuse as main transcript	c.-289C>A		5_prime_UTR_variant	2/10		NP_001268697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ADCY1	ENST00000297323.12 linkuse as main transcript	c.387C>A	p.Phe129Leu	missense_variant	1/20	1	NM_021116.4	ENSP00000297323	P1
ADCY1	ENST00000432715.5 linkuse as main transcript	c.-289C>A		5_prime_UTR_variant	2/10	2		ENSP00000392721
ADCY1	ENST00000621543.1 linkuse as main transcript	c.-289C>A		5_prime_UTR_variant	1/9	5		ENSP00000479770

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000411

AC:

AN:

243438

Hom.:

AF XY:

0.00000749

AC XY:

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:

AN:

1459700

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

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.:

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 submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The 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

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.0

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.41

Sift

Benign

0.36

Sift4G

Benign

0.26

Polyphen

0.64

Vest4

0.39

MutPred

0.62

Loss of catalytic residue at F129 (P = 0.0639);

MVP

0.67

MPC

1.4

ClinPred

0.52

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over