Genetic Variant AVEN:p.Asp46Tyr (chr15-34038911-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020371.3(AVEN):c.136G>T(p.Asp46Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AVEN
NM_020371.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.74

Publications

0 publications found

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]

AVEN links:

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]

CHRM5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020371.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AVEN	NM_020371.3	MANE Select	c.136G>T	p.Asp46Tyr	missense	Exon 1 of 6	NP_065104.1	Q9NQS1
CHRM5	NM_012125.4	MANE Select	c.-407-7629C>A		intron	N/A	NP_036257.1	P08912
CHRM5	NM_001320917.2		c.-75-23732C>A		intron	N/A	NP_001307846.1	P08912

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AVEN	ENST00000306730.8	TSL:1 MANE Select	c.136G>T	p.Asp46Tyr	missense	Exon 1 of 6	ENSP00000306822.3	Q9NQS1
CHRM5	ENST00000383263.7	TSL:2 MANE Select	c.-407-7629C>A		intron	N/A	ENSP00000372750.5	P08912
CHRM5	ENST00000557872.1	TSL:1	c.-76+20446C>A		intron	N/A	ENSP00000453745.1	P08912

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

968894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

459398

African (AFR)

AF:

0.00

AC:

AN:

18512

American (AMR)

AF:

0.00

AC:

AN:

4998

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9236

East Asian (EAS)

AF:

0.00

AC:

AN:

12828

South Asian (SAS)

AF:

0.00

AC:

AN:

19054

European-Finnish (FIN)

AF:

0.00

AC:

AN:

13606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

853072

Other (OTH)

AF:

0.00

AC:

AN:

35294

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.022

Eigen

Benign

0.071

Eigen_PC

Benign

0.032

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.24

M_CAP

Pathogenic

0.52

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.90

PhyloP100

1.7

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.87

REVEL

Benign

0.16

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.034

Polyphen

0.99

Vest4

0.34

MutPred

0.27

Gain of phosphorylation at D46 (P = 0.0714)

MVP

0.62

MPC

0.0010

ClinPred

0.57

GERP RS

2.3

PromoterAI

0.035

Neutral

(source)

Varity_R

0.21

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.32

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over