15-34038850-C-A

Variant names:

• chr15-34038850-C-A
• rs1402695265
• NM_020371.3:c.197G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020371.3(AVEN):​c.197G>T​(p.Arg66Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000985 in 1,015,664 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R66Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.8e-7 (0 hom.)
• Consequence: AVEN NM_020371.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.470
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27197155).

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.197G>T	p.Arg66Leu	missense	Exon 1 of 6	NP_065104.1	Q9NQS1
	CHRM5	NM_012125.4	MANE Select	c.-407-7690C>A		intron	N/A	NP_036257.1	P08912
	CHRM5	NM_001320917.2		c.-75-23793C>A		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.197G>T	p.Arg66Leu	missense	Exon 1 of 6	ENSP00000306822.3	Q9NQS1
	CHRM5	ENST00000383263.7	TSL:2 MANE Select	c.-407-7690C>A		intron	N/A	ENSP00000372750.5	P08912
	CHRM5	ENST00000557872.1	TSL:1	c.-76+20385C>A		intron	N/A	ENSP00000453745.1	P08912

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.85e-7 AC: 1 AN: 1015664 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 482452

African (AFR) AF: 0.00 AC: 0 AN: 19582

American (AMR) AF: 0.00 AC: 0 AN: 6684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10764

East Asian (EAS) AF: 0.00 AC: 0 AN: 18874

South Asian (SAS) AF: 0.00 AC: 0 AN: 20642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2508

European-Non Finnish (NFE) AF: 0.00000113 AC: 1 AN: 881406

Other (OTH) AF: 0.00 AC: 0 AN: 38040

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.035	T
Eigen	Benign	0.10
Eigen_PC	Benign	0.023
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.32	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.47
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.12
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.16	T
Polyphen		0.99	D
Vest4		0.25
MutPred		0.33		Loss of methylation at R66 (P = 2e-04)
MVP		0.67
MPC		0.00099
ClinPred		0.76	D
GERP RS		2.1
PromoterAI		0.21	Neutral
Varity_R		0.15
gMVP		0.23
Mutation Taster		=92/8	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: rs1402695265; hg19: chr15-34331051;