1-40629358-C-T

Position:

• chr1-40629358-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014747.3(RIMS3):​c.487G>A​(p.Ala163Thr) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RIMS3 NM_014747.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77

Genes affected

RIMS3 (HGNC:21292): (regulating synaptic membrane exocytosis 3) Predicted to enable transmembrane transporter binding activity. Predicted to be involved in several processes, including calcium ion-regulated exocytosis of neurotransmitter; modulation of chemical synaptic transmission; and regulation of synapse organization. Predicted to be located in presynaptic active zone. Predicted to be part of glutamatergic synapse. Predicted to be active in cytoskeleton of presynaptic active zone; postsynaptic cytosol; and presynaptic membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25610524).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIMS3	NM_014747.3	c.487G>A	p.Ala163Thr	missense_variant	6/8	ENST00000372684.8
RIMS3	XM_047435184.1	c.487G>A	p.Ala163Thr	missense_variant	9/11
RIMS3	XM_047435189.1	c.487G>A	p.Ala163Thr	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIMS3	ENST00000372684.8	c.487G>A	p.Ala163Thr	missense_variant	6/8	1	NM_014747.3	P1
RIMS3	ENST00000372683.1	c.487G>A	p.Ala163Thr	missense_variant	6/8	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2022

The c.487G>A (p.A163T) alteration is located in exon 6 (coding exon 4) of the RIMS3 gene. This alteration results from a G to A substitution at nucleotide position 487, causing the alanine (A) at amino acid position 163 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.049	T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.055
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.94	L;L
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.23
Sift	Benign	0.052	T;T
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.22	B;B
Vest4		0.25
MutPred		0.44		Gain of disorder (P = 0.2965);Gain of disorder (P = 0.2965);
MVP		0.87
MPC		0.34
ClinPred		0.81	D
GERP RS		4.7
Varity_R		0.17
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1287483760; hg19: chr1-41095030;