15-34038886-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_020371.3(AVEN):​c.161G>T​(p.Gly54Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000263 in 1,139,598 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: 𝑓 0.0000067 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000020 ( 0 hom. )

Consequence

AVEN
NM_020371.3 missense

Scores

3
4
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.32
Variant links:
Genes affected
AVEN (HGNC:13509): (apoptosis and caspase activation inhibitor) Involved in negative regulation of apoptotic process. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]
CHRM5 (HGNC:1954): (cholinergic receptor muscarinic 5) The muscarinic cholinergic receptors belong to a larger family of G protein-coupled receptors. The functional diversity of these receptors is defined by the binding of acetylcholine and includes cellular responses such as adenylate cyclase inhibition, phosphoinositide degeneration, and potassium channel mediation. Muscarinic receptors influence many effects of acetylcholine in the central and peripheral nervous system. The clinical implications of this receptor are unknown; however, stimulation of this receptor is known to increase cyclic AMP levels. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.38348684).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AVENNM_020371.3 linkc.161G>T p.Gly54Val missense_variant Exon 1 of 6 ENST00000306730.8 NP_065104.1 Q9NQS1
CHRM5NM_012125.4 linkc.-407-7654C>A intron_variant Intron 1 of 2 ENST00000383263.7 NP_036257.1 P08912A0A024R9I2Q8IVW0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AVENENST00000306730.8 linkc.161G>T p.Gly54Val missense_variant Exon 1 of 6 1 NM_020371.3 ENSP00000306822.3 Q9NQS1
CHRM5ENST00000383263.7 linkc.-407-7654C>A intron_variant Intron 1 of 2 2 NM_012125.4 ENSP00000372750.5 P08912

Frequencies

GnomAD3 genomes
AF:
0.00000672
AC:
1
AN:
148822
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000244
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000202
AC:
2
AN:
990776
Hom.:
0
Cov.:
29
AF XY:
0.00000213
AC XY:
1
AN XY:
470058
show subpopulations
Gnomad4 AFR exome
AF:
0.000105
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
AF:
0.00000672
AC:
1
AN:
148822
Hom.:
0
Cov.:
32
AF XY:
0.0000138
AC XY:
1
AN XY:
72522
show subpopulations
Gnomad4 AFR
AF:
0.0000244
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 01, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.161G>T (p.G54V) alteration is located in exon 1 (coding exon 1) of the AVEN gene. This alteration results from a G to T substitution at nucleotide position 161, causing the glycine (G) at amino acid position 54 to be replaced by a valine (V). 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
Uncertain
0.37
BayesDel_addAF
Uncertain
0.059
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.035
T
Eigen
Benign
0.076
Eigen_PC
Benign
0.028
FATHMM_MKL
Benign
0.44
N
LIST_S2
Benign
0.30
T
M_CAP
Pathogenic
0.50
D
MetaRNN
Benign
0.38
T
MetaSVM
Benign
-0.86
T
MutationAssessor
Benign
2.0
M
PrimateAI
Pathogenic
0.94
D
PROVEAN
Benign
-1.3
N
REVEL
Benign
0.11
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0090
D
Polyphen
1.0
D
Vest4
0.34
MutPred
0.35
Gain of sheet (P = 0.0085);
MVP
0.74
MPC
0.00098
ClinPred
0.93
D
GERP RS
2.3
Varity_R
0.15
gMVP
0.37

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

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

Other links and lift over

dbSNP: rs1271152787; hg19: chr15-34331087; API