15-34038917-C-G

Variant names:

• chr15-34038917-C-G
• rs1201476939
• NM_020371.3:c.130G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_020371.3(AVEN):​c.130G>C​(p.Gly44Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000021 in 714,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G44S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000096 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: AVEN NM_020371.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.265
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08412871).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AVEN	NM_020371.3	MANE Select	c.130G>C	p.Gly44Arg	missense	Exon 1 of 6	NP_065104.1	Q9NQS1
	CHRM5	NM_012125.4	MANE Select	c.-407-7623C>G		intron	N/A	NP_036257.1	P08912
	CHRM5	NM_001320917.2		c.-75-23726C>G		intron	N/A	NP_001307846.1	P08912

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AVEN	ENST00000306730.8	TSL:1 MANE Select	c.130G>C	p.Gly44Arg	missense	Exon 1 of 6	ENSP00000306822.3	Q9NQS1
	CHRM5	ENST00000383263.7	TSL:2 MANE Select	c.-407-7623C>G		intron	N/A	ENSP00000372750.5	P08912
	CHRM5	ENST00000557872.1	TSL:1	c.-76+20452C>G		intron	N/A	ENSP00000453745.1	P08912

Frequencies

GnomAD3 genomes AF: 0.00000956 AC: 1 AN: 104610 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000200

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: 0.0000230 AC: 14 AN: 609840 Hom.: 0 Cov.: 4 AF XY: 0.0000138 AC XY: 4 AN XY: 288816

African (AFR) AF: 0.00 AC: 0 AN: 15718

American (AMR) AF: 0.00 AC: 0 AN: 3466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3556

East Asian (EAS) AF: 0.00124 AC: 14 AN: 11288

South Asian (SAS) AF: 0.00 AC: 0 AN: 15470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1202

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 530138

Other (OTH) AF: 0.00 AC: 0 AN: 22382

GnomAD4 genome AF: 0.00000956 AC: 1 AN: 104610 Hom.: 0 Cov.: 29 AF XY: 0.0000196 AC XY: 1 AN XY: 50898

African (AFR) AF: 0.00 AC: 0 AN: 35034

American (AMR) AF: 0.00 AC: 0 AN: 10510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1368

East Asian (EAS) AF: 0.000200 AC: 1 AN: 4994

South Asian (SAS) AF: 0.00 AC: 0 AN: 3950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 166

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 41542

Other (OTH) AF: 0.00 AC: 0 AN: 1398

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.27
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.062
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.43	T
Polyphen		0.0070	B
Vest4		0.23
MutPred		0.47		Gain of methylation at G44 (P = 8e-04)
MVP		0.42
MPC		0.0010
ClinPred		0.74	D
GERP RS		-1.7
PromoterAI		-0.00010	Neutral
Varity_R		0.21
gMVP		0.10
Mutation Taster		=90/10	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: rs1201476939; hg19: chr15-34331118;