15-34038904-C-T

Variant names:

• chr15-34038904-C-T
• rs1188896353
• NM_020371.3:c.143G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020371.3(AVEN):​c.143G>A​(p.Gly48Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000258 in 1,123,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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: 0.000029 (0 hom.)
• Consequence: AVEN NM_020371.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.501
• Publications: 0 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05338514).

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.143G>A	p.Gly48Asp	missense	Exon 1 of 6	NP_065104.1	Q9NQS1
	CHRM5	NM_012125.4	MANE Select	c.-407-7636C>T		intron	N/A	NP_036257.1	P08912
	CHRM5	NM_001320917.2		c.-75-23739C>T		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.143G>A	p.Gly48Asp	missense	Exon 1 of 6	ENSP00000306822.3	Q9NQS1
	CHRM5	ENST00000383263.7	TSL:2 MANE Select	c.-407-7636C>T		intron	N/A	ENSP00000372750.5	P08912
	CHRM5	ENST00000557872.1	TSL:1	c.-76+20439C>T		intron	N/A	ENSP00000453745.1	P08912

Frequencies

GnomAD3 genomes AF: 0.00000673 AC: 1 AN: 148484 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000150

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000926 AC: 1 AN: 1080 AF XY: 0.00157

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00175

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 28 AN: 975414 Hom.: 0 Cov.: 29 AF XY: 0.0000389 AC XY: 18 AN XY: 462656

African (AFR) AF: 0.00 AC: 0 AN: 18660

American (AMR) AF: 0.00 AC: 0 AN: 5098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9460

East Asian (EAS) AF: 0.00 AC: 0 AN: 13546

South Asian (SAS) AF: 0.00 AC: 0 AN: 19106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2306

European-Non Finnish (NFE) AF: 0.0000315 AC: 27 AN: 857322

Other (OTH) AF: 0.0000280 AC: 1 AN: 35722

GnomAD4 genome AF: 0.00000673 AC: 1 AN: 148484 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72346

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41030

American (AMR) AF: 0.00 AC: 0 AN: 14948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3408

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66596

Other (OTH) AF: 0.00 AC: 0 AN: 2040

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

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	0.21
BayesDel_addAF	Benign	-0.0076	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.26	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.50
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.088
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.16	T
Polyphen		0.031	B
Vest4		0.24
MutPred		0.23		Loss of catalytic residue at G48 (P = 0.0927)
MVP		0.40
MPC		0.00095
ClinPred		0.21	T
GERP RS		1.3
PromoterAI		-0.062	Neutral
Varity_R		0.30
gMVP		0.35
Mutation Taster		=87/13	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: rs1188896353; hg19: chr15-34331105;