15-74826818-A-T

Variant names:

• chr15-74826818-A-T
• rs761543817
• NM_001030005.3:c.115A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001030005.3(CPLX3):​c.115A>T​(p.Met39Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CPLX3 NM_001030005.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.81

Genes affected

CPLX3 (HGNC:27652): (complexin 3) Predicted to enable SNARE binding activity. Predicted to be involved in regulation of neurotransmitter secretion and synaptic vesicle exocytosis. Predicted to be located in plasma membrane and synapse. Predicted to be part of SNARE complex. Predicted to be active in photoreceptor ribbon synapse and terminal bouton. Predicted to be anchored component of presynaptic active zone membrane and anchored component of synaptic vesicle membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000261606 (HGNC:):

ACMG classification

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=0.40580112).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPLX3	NM_001030005.3	c.115A>T	p.Met39Leu	missense_variant	Exon 1 of 3	ENST00000395018.6	NP_001025176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPLX3	ENST00000395018.6	c.115A>T	p.Met39Leu	missense_variant	Exon 1 of 3	1	NM_001030005.3	ENSP00000378464.4
ENSG00000261606	ENST00000488000.6	n.3324A>T		non_coding_transcript_exon_variant	Exon 12 of 14	2
ENSG00000261606	ENST00000564823.1	n.3553A>T		non_coding_transcript_exon_variant	Exon 4 of 6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452668 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722754

Gnomad4 AFR exome AF: 0.00

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.049	D
Polyphen		0.70	P
Vest4		0.49
MutPred		0.43		Loss of phosphorylation at Y44 (P = 0.4133);
MVP		0.70
MPC		0.81
ClinPred		0.92	D
GERP RS		4.3
Varity_R		0.62
gMVP		0.45

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

Other links and lift over

dbSNP: rs761543817; hg19: chr15-75119159; COSMIC: COSV59001436; COSMIC: COSV59001436;